2-Heteroarylcarboxylic acid amides

ABSTRACT

The invention relates to novel 2-heteroarylcarboxamides, processes for their preparation, and their use for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning and/or memory.

The invention relates to novel 2-heteroarylcarboxamides, processes fortheir preparation, and their use for producing medicaments for thetreatment and/or prophylaxis of diseases and for improving perception,concentration, learning and/or memory.

Nicotinic acetylcholine receptors (nAChR) form a large family of ionchannels which are activated by the messenger acetylcholine which isproduced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34,563-582). A functional nAChR consists of five subunits which may bedifferent (certain combinations of α1-9 and β1-4,γ,δ,ε subunits) oridentical (α7-9). This leads to the formation of a diversity of subtypeswhich differ in the distribution in the muscles, the nervous system andother organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).Activation of nAChR leads to influx of cations into the cell and tostimulation of nerve cells or muscle cells. Selective activation ofindividual nAChR subtypes restricts this stimulation to the cell typeswhich have a corresponding subtype and is thus able to avoid unwantedside effects such as, for example, stimulation of nAChR in the muscles.Clinical experiments with nicotine and experiments in various animalmodels indicate that central nicotinic acetylcholine receptors areinvolved in learning and memory processes (e.g. Rezvani and Levin, Biol.Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of thealpha7 subtype (α7 nAChR) have a particularly high concentration inregions of the brain which are important for learning and memory, suchas the hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci.1993, 13, 596-604). The α7 nAChR has a particularly high permeabilityfor calcium ions, increases glutamatergic neurotransmission, influencesthe growth of axons and, in this way, modulates neuronal plasticity(Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).

Certain N-(1-azabicyclo[2.2.2]oct-3-yl)heteroaryl carboxamides for thetreatment of, inter alia, psychoses are described in DE-A 37 24 059.

N-(Azabicycloalkyl)heteroaryl carboxamides, in particularN-(1-azabicyclo-[2.2.2]oct-4-yl)benzothiophene-3-carboxamides, aredisclosed in WO 93/15073 and in EP-A 0 485 962 as intermediates for thesynthesis of pharmaceutically active compounds.

1-Azabicycloalkanes and their action on the nicotinic α7-receptor areknown from JP 14030084A.

U.S. Pat. No. 4,605,652 and EP-A 0 372 335 disclose, for example,N-(1-azabicyclo[2.2.2]oct-3-yl)thiophene-2-carboxamide and itsmemory-improving effect.

The present invention relates to compounds of the formula (I)

in which

-   -   R¹ represents 1-azabicyclo[2.2.2]oct-3-yl,    -   R² represents hydrogen or C₁-C₆-alkyl,    -   R³ represents hydrogen, halogen or C₁-C₆-alkyl,    -   A represents oxygen or sulfur,    -   and    -   the ring B represents benzo, pyrido, pyrimido, pyridazo or        pyridazino which are optionally substituted by radicals selected        from the group consisting of hydrogen, halogen, C₁-C₆-alkanoyl,        carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro,        amino, C₁-C₆-acylamino, C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₁-C₆-alkylthio, C₁-C₆-alkylamino, heteroarylcarbonylamino,        arylcarbonylamino, C₁-C₄-alkylsulfonylamino,        di-(C₁-C₄-alkyl-sulfonyl)amino, arylsulfonylamino,        di(arylsulfonyl)amino, C₃-C₆-cycloalkylcarbonylmethyl,        1,3-dioxapropane-1,3-diyl, amino(hydroxy-imino)methyl and benzo,    -   and their salts, solvates and solvates of the salts.

The compounds according to the invention can exist in stereoisomericforms which are either like image and mirror image (enantiomers) orwhich are not like image and mirror image (diastereomers). The inventionrelates both to the enantiomers and diastereomers and to theirrespective mixtures. These mixtures of the enantiomers and diastereomerscan be separated in a known manner into the stereoisomeric uniformcomponents.

Compounds according to the invention can also be present in the form oftheir salts, solvates or solvates of the salts.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds according to theinvention may be acid addition salts of the compounds with mineralacids, carboxylic acids or sulfonic acids. Particularly preferredexamples are salts with hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid,acetic acid, propionic acid, lactic acid, tartaric acid, citric acid,fumaric acid, maleic acid or benzoic acid.

However, salts which may be mentioned are also salts with conventionalbases, such as, for example, alkali metal salts (e.g. sodium orpotassium salts), alkaline earth metal salts (e.g. calcium or magnesiumsalts) or ammonium salts derived from ammonia or organic amines such as,for example, diethylamine, triethylamine, ethyldiisopropylamine,procaine, dibenzylamine, N-methylmorpholine, dihydro-abiethylamine,1-ephenamine or N-methylpiperidine.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds which form a complex with solvent molecules bycoordination in the solid or liquid state. Hydrates are a special formof solvates in which the coordination takes place with water.

For the purposes of the present invention, the substituents generallyhave the following meaning:

C₁-C₆- and C₁-C₄-Alkoxy are a straight-chain or branched alkoxy radicalhaving 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is givento a straight-chain or branched alkoxy radical having 1 to 4,particularly preferably 1 to 3, carbon atoms. The following radicals maybe mentioned by way of example and by way of preference: methoxy,ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

C₁-C6- and C₁-C₄-Alkyl are a straight-chain or branched alkyl radicalhaving 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is givento a straight-chain or branched alkyl radical having 1 to 4,particularly preferably 1 to 3, carbon atoms. The following radicals maybe mentioned by way of example and by way of preference: methyl, ethyl,n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C₁-C₆)-Alkanoyl is a straight-chain or branched alkyl radical having 1to 6 carbon atoms which carries a doubly attached oxygen atom in the1-position and is attached via the 1-position. Preference is given to astraight-chain or branched alkanoyl radical having 1 to 4, particularlypreferably 1 to 2, carbon atoms. The following radicals may be mentionedby way of example and by way of preference: formyl, acetyl, propionyl,n-butyryl, isobutyryl, pivaloyl and n-hexanoyl.

C₁-C₆-Alkylamino is a straight-chain or branched alkylamino radicalhaving 1 to 6 carbon atoms, preferably 1 to 4, particularly preferably 1to 3, carbon atoms. Nonlimiting examples include methylamino,ethylamino, n-propylamino, isopropylamino and tert-butylamino.

(C₁-C₆)-Acylamino is an amino group having a straight-chain or branchedalkanoyl substituent which has 1 to 6 carbon atoms and is attached viathe carbonyl group. Preference is given to an acylamino radical having 1to 4, particularly preferably 1 to 2, carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

C₁-C₄-Alkylsulfonylamino is a straight-chain or branchedalkylsulfonylamino radical having 1 to 4, preferably 1 to -3, carbonatoms. Nonlimiting examples include methylsulfonylamino,ethylsulfonylamino, n-propylsulfonylamino, isopropyl-sulfonylamino,tert-butylsulfonylamino.

Arylsulfonylamino is a naphthyl- or phenylsulfonylamino radical andpreferably a phenylsulfonylamino radical.

C₁-C₆-Alkylthio is a straight-chain or branched alkylthio radicalhaving 1. to 6 carbon atoms. Preference is given to a straight-chain orbranched alkylthio radical having 1 to 4, particularly preferably 1 to3, carbon atoms. The following radicals may be mentioned by way ofexample and by way of preference: methylthio, ethylthio, n-propylthio,isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Arylcarbonyl is a naphthyl- or phenylcarbonyl radical and preferably aphenylcarbonyl radical (Benzoyl radical).

Heteroarylcarbonyl is a heteroarylcarbonyl radical having a 5- to6-membered, preferably a 5-membered, heteroaryl ring having up to 2heteroatoms selected from the group consisting of O, S and N.Nonlimiting examples include thienylcarbonyl, furylcarbonyl,pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl,imidazolylcarbonyl, pyridylcarbonyl, pyrimidylcarbonyl.

C₃-C₆-Cycloalkylcarbonylmethyl is a monocyclic cycloalkyl group having 3to 6 carbon atoms which is attached via a carbonylmethyl group[—C(═O)—CH₂—]. Nonlimiting examples include cyclopropylcarbonylmethyl,cyclopentylcarbonylmethyl and cyclohexylcarbonylmethyl.

Halogen is fluorine, chlorine, bromine and iodine. Preference is givento fluorine, chlorine and bromine. Particular preference is given tofluorine and chlorine.

When radicals in the compounds according to the invention are optionallysubstituted, unless indicated otherwise the radicals may have one ormore identical or different substituents. Preference is given toradicals substituted by up to three identical or different substituents.

Preference is given to compounds of the formula (I),

-   -   in which    -   R¹ represents 1-azabicyclo[2.2.2]oct-3-yl,    -   R² represents hydrogen or (C₁-C₆)-alkyl,    -   R³ represents hydrogen, halogen or (C₁-C₆)-alkyl,    -   A represents oxygen or sulfur,    -   and    -   the ring B represents benzo, pyrido, pyrimido, pyridazo or        pyridazino which are optionally substituted by radicals selected        from the group consisting of hydrogen, halogen, formyl,        carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro,        amino, formamido, acetamido, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,        (C₁-C₆)-alkylthio and benzo.

Particular preference is given to compounds of the formula (I),

-   -   in which    -   R¹ represents 1-azabicyclo[2.2.2]oct-3-yl,    -   R² represents hydrogen,    -   R³ represents hydrogen, chlorine, fluorine or methyl,    -   A represents oxygen or sulfur,    -   and    -   the ring B represents benzo or pyrido, where benzo or pyrido is        optionally substituted by 1 to 3 radicals selected from the        group consisting of hydrogen, halogen, formyl, carbamoyl, cyano,        trifluoromethyl, trifluoromethoxy, nitro, amino, formamido,        acetamido, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio,        C₁-C₄-alkylamino, furylcarbonylamino, phenylcarbonylamino,        methylsulfonylamino, di(phenylsulfonyl)amino,        cyclopropylcarbonylmethyl, 1,3-dioxapropane-1,3-diyl,        amino(hydroxyimino)methyl and benzo.

Especially preferred are compounds of the formula (Ia)

-   -   in which    -   R¹ represents 1-azabicyclo[2.2.2]oct-3-yl,    -   R² represents hydrogen or C₁-C₆-alkyl,    -   R³ represents hydrogen, halogen or C₁-C₆-alkyl,    -   A represents oxygen or sulfur,    -   and    -   Z represents hydrogen, halogen, formyl, carbamoyl, cyano,        trifluoromethyl, trifluoromethoxy, nitro, amino, formamido,        acetamido, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio,        C₁-C₆-alkylamino, heteroarylcarbonylamino, arylcarbonylamino,        C₁-C₄-alkylsulfonylamino, di(arylsulfonyl)amino,        C₃-C₆-cycloalkylcarbonylmethyl or amino(hydroxyimino)methyl.

Very particular preference is given to compounds of the formula (Ia),

-   -   in which    -   R¹ represents 1-azabicyclo[2.2.2]oct-3-yl,    -   R² represents hydrogen,    -   R³ represents hydrogen, chlorine, fluorine or methyl,    -   A represents oxygen or sulfur,    -   and    -   Z represents hydrogen, halogen, formyl, carbamoyl, cyano,        trifluoromethyl, trifluoromethoxy, nitro, amino, formamido,        acetamido, methyl, ethyl, methoxy, ethoxy, C₁-C₄-alkylamino,        furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino,        di(phenylsulfonyl)amino, cyclopropylcarbonylmethyl or        amino(hydroxyimino)methyl.

Particularly preferred are compounds of the formula (Ia),

-   -   in which    -   R¹ represents (3R)-1-azabicyclo[2.2.2]oct-3-yl,    -   R² represents hydrogen,    -   R³ represents hydrogen, chlorine, fluorine or methyl,    -   A represents oxygen or sulfur,    -   and    -   Z represents hydrogen, halogen, formyl, carbamoyl, cyano,        trifluoromethyl, trifluoromethoxy, nitro, amino, formamido,        acetamido, methyl, ethyl, methoxy, ethoxy, C₁-C₄-alkylamino,        furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino,        di(phenylsulfonyl)amino, cyclopropylcarbonylmethyl or        amino(hydroxyimino)methyl.

Also preferred are compounds of the formula (I),

-   -   in which    -   R¹ represents (3R)-1-azabicyclo[2.2.2]oct-3-yl,    -   and R², R³, A and the ring B are as defined above.

Particularly preferred are compounds of the formula (Ia),

-   -   in which    -   R¹ represents (3R)-1-azabicyclo[2.2.2]oct-3-yl,    -   and R², R³, A and Z are as defined above.

Also preferred are compounds of the formula (I),

-   -   in which    -   R² represents hydrogen or methyl,    -   and R¹, R³, A and the ring B are as defined above.

Particularly preferred are compounds of the formula (I),

-   -   in which    -   R² represents hydrogen,    -   and R¹, R³, A and the ring B are as defined above.

Also preferred are compounds of the formula (I),

-   -   in which    -   R³ represents hydrogen, fluorine, chlorine or methyl,    -   and R¹, R², A and the ring B are as defined above.

Particularly preferred are compounds of the formula (I),

-   -   in which    -   R³ represents hydrogen or methyl,    -   and R¹, R², A and the ring B are as defined above.

Very particularly preferred are compounds of the formula (I),

-   -   in which    -   R³ represents hydrogen,    -   and R¹, R², A and the ring B are as defined above.

Also preferred are compounds of the formula (I),

-   -   in which    -   A represents sulfur,    -   and R¹, R², R³ and the ring B are as defined above.

Also preferred are compounds of the formula (I),

-   -   in which    -   A represents oxygen,    -   and R¹, R², R³ and the ring B are as defined above.

Particularly preferred are compounds of the formula (Ia),

-   -   in which    -   A represents sulfur,    -   and R¹, R², R³ and Z are as defined above.

Also particularly preferred are compounds of the formula (Ia),

-   -   in which    -   A represents oxygen,    -   and R¹, R², R³ and Z are as defined above.

Also preferred are compounds of the formula (I),

-   -   in which    -   the ring B represents benzo or pyrido, where benzo and pyrido        are optionally substituted by 1 to 3 radicals selected from the        group consisting of hydrogen, halogen, formyl, carbamoyl, cyano,        trifluoromethyl, trifluoromethoxy, nitro, amino, formamido,        acetamido, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio,        C₁-C₄-alkylamino, farylcarbonylamino, phenylcarbonylamino,        methylsulfonylamino, di(phenylsulfonyl)amino,        cyclopropylcarbonylmethyl and amino(hydroxyimino)methyl,    -   and R¹, R², R³ and A are as defined above.

Particularly preferred are compounds of the formula (I),

-   -   in which    -   the ring B represents benzo or pyrido, where benzo and pyrido        are optionally substituted by 1 to 3 radicals selected from the        group consisting of hydrogen, halogen, cyano, trifluoromethyl,        trifluoromethoxy, nitro, amino, formamido, acetamido and        (C₁-C₄)-alkyl,    -   and R¹, R², R³ and A are as defined above.

Very particular preference is given to compounds of formula (I),

-   -   in which    -   the ring B represents benzo, where benzo is optionally        substituted by 1 to 3 radicals selected from the group        consisting of hydrogen, halogen, cyano, trifluoromethyl,        trifluoromethoxy, nitro, amino, formamido, acetamido and        (C₁-C₄)-alkyl,    -   and R¹, R², R³ and A are as defined above.

Also particularly preferred are compounds of the formula (Ia),

-   -   in which    -   Z represents hydrogen, halogen, formyl, carbamoyl, cyano,        trifluoromethyl, trifluoromethoxy, nitro, amino, formamido,        acetamido, methyl, ethyl, methoxy, ethoxy, C₁-C₄-alkylamino,        furylcarbonylamino, phenylcarbonyl-amino, methylsulfonylamino,        di(phenylsulfonyl)amino, cyclopropylcarbonyl-methyl or        amino(hydroxyimino)methyl,    -   and R¹, R², R³ and A are as defined above.

Very particular preference is given to combinations of two or more ofthe preferred ranges mentioned above.

Especially preferred are compounds of the formula (I),

-   -   in which    -   R¹ represents (3R)-1-azabicyclo[2.2.2]oct-3-yl,    -   R² and R³ represent hydrogen,    -   A represents sulfur,    -   and    -   the ring B represents benzo or pyrido, where benzo and pyrido        are optionally substituted by 1 to 3 radicals selected from the        group consisting of hydrogen, halogen, cyano, trifluoromethyl,        trifluoromethoxy, nitro, amino, formamido, acetamido and        (C₁-C₄)-alkyl.

The invention relates furthermore to a process for preparing thecompounds of the formula (I), characterized in that compounds of theformula (II)R¹R²NH   (II),in which R¹ and R² are as defined above

-   -   are reacted with a compound of the formula (III)        in which    -   R³, A and the ring B are as defined above, and    -   X represents hydroxy or a suitable leaving group,    -   in an inert solvent, if appropriate in the presence of a        condensing agent and if appropriate in the presence of a base.

If X represents a leaving group, preference is given to chlorine,mesyloxy and isobutyloxycarbonyloxy, in particular to chlorine.

Inert solvents are, for example, halogenated hydrocarbons, such asmethylene chloride, trichloromethane, carbon tetrachloride,trichloroethane, tetrachloroethane, 1,2-dichloroethane ortrichloroethylene, ethers, such as diethyl ether, methyl tert-butylether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethyleneglycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene,hexane, cyclohexane or mineral oil fractions, or other solvents, such asnitromethane, ethyl acetate, acetone, dimethylformamide,dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrileor pyridine; preference is given to tetrahydrofuran, dimethylformamideor chloroform.

Condensing agents are, for example, carbodiimides, such as, for example,N,N′-diethyl-, N,N,′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexyl-carbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide), or carbonyl compounds, such as carbonyldiimidazole,or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylaminocompounds, such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis-(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)-phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these.

If appropriate, it may be advantageous to use these condensing agents inthe presence of an auxiliary nucleophile, such as, for example,1-hydroxybenzotriazole (HOBt).

Bases are, for example, alkali metal carbonates, such as, for example,sodium carbonate or potassium carbonate or sodium bicarbonate orpotassium bicarbonate, or organic bases, such as trialkylamines, forexample triethylamine, N-methylmorpholine, N-methylpiperidine,4-N,N-dimethylaminopyridine or N,N-diisopropylethylamine.

Preference is given toO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in the presence of N,N-diisopropylethylamineand to the combination ofN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)and 1-hydroxybenzotriazole (HOBt), in each case in dimethylformamide.

The process according to the invention is preferably carried out in atemperature range of from room temperature to 50° C., at atmosphericpressure.

The compounds of the formulae (II) and (III) are known or can besynthesized by known processes from the appropriate starting materials(cf., for example, “Comprehensive Heterocyclic Chemistry”, Katritzki etal., Ed.; Elsevier, 1996).

Thus, for example, substituted benzothiophene-2-carboxylic acids can beobtained from appropriately substituted 2-halobenzaldehydes by reactionwith methyl mercaptoacetate (see, for example, A. J. Bridges, A. Lee, E.C. Maduakor, Schwartz, Tetrahedron Lett. 1992, 33, 7499) and subsequenthydrolysis of the ester (synthesis scheme 1):

To synthesize the corresponding pyrido derivatives, it is possible toreact 2-halo-benzonitrile starting materials with methyl mercaptoacetateto give the 3-aminobenzothiophene-2-carboxylic esters (synthesis scheme2). The amino function can be removed by diazotization. Finally, theester is hydrolyzed to give the target compound:

Substituted benzofuran-2-carboxylic acids can be obtained, for example,in accordance with D. Bogdal, M. Warzala, Tetrahedron 2000, 56, 8769(synthesis scheme 3):

The compounds according to the invention of the formula (I) are suitablefor use as medicaments for the treatment and/or prophylaxis of diseasesin humans and/or animals.

The compounds according to the invention have an unforeseeable, usefulpharmacological activity spectrum.

They act as ligands, in particular as α7-nAChR agonists.

The compounds of the invention can, because of their pharmacologicalproperties, be employed alone or in combination with other activeingredients for the treatment and/or prevention of cognitiveimpairments, especially of Alzheimer's disease. Because of theirselective effect as α7-nAChR agonists, the compounds of the inventionare particularly suitable for improving perception, concentration,learning or memory, especially after cognitive impairments like thoseoccurring for example in situations/diseases/syndromes such as mildcognitive impairment, age-associated learning and memory impairments,age-associated memory loss, vascular dementia, craniocerebral trauma,stroke, dementia occurring after strokes (post-stroke dementia),post-traumatic brain syndrome, general concentration impairments,concentration impairments in children with learning and memory problems,attention deficit hyperactivity disorder, Alzheimer's disease, Lewy bodydementia, dementia with degeneration of the frontal lobes, includingPick's syndrome, Parkinson's disease, progressive nuclear palsy,dementia with corticobasal degeneration, amyotrophic lateral sclerosis(ALS), Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jakob dementia, HIV dementia, schizophrenia, schizophreniawith dementia or Korsakoff s psychosis.

The compounds of the invention can be employed alone or in combinationwith other active ingredients for the prophylaxis and treatment of acuteand/or chronic pain (for a classification, see “Classification ofChronic Pain, Descriptions of Chronic Pain Syndromes and Definitions ofPain Terms”, 2nd edition, Meskey and Begduk, editors; IASP Press,Seattle, 1994), especially for the treatment of cancer-induced pain andchronic neuropathic pain like, for example, that associated withdiabetic neuropathy, postherpetic neuralgia, peripheral nerve damage,central pain (for example as a consequence of cerebral ischaemia) andtrigeminal neuralgia, and other chronic pain such as, for example,lumbago, backache (low back pain) or rheumatic pain. In addition, theseactive ingredients are also suitable for the therapy of primary acutepain of any origin and of secondary states of pain resulting therefrom,and for the therapy of states of pain which were formerly acute and havebecome chronic.

The in vitro effect of the compounds of the invention can be shown inthe following assays:

1. Determination of the Affinity of Test Substances for α7-nAChR byInhibition of [³H]-methyllycaconitine Binding to Rat Brain Membranes

The [³H]-methyllycaconitine binding assay is a modification of themethod described by Davies et al. in Neuropharmacol. 1999, 38, 679-690.

Rat brain tissue (hippocampus or whole brain) is homogenized inhomogenization buffer (10% w/v, 0.32 M sucrose, 1 mM EDTA, 0.1 mMphenylmethylsulfonyl fluoride (PMSF), 0.01% (w/v) NaN₃, pH 7.4, 4° C.)at 600 rpm in a glass homogenizer. The homogenate is centrifuged(1000×g, 4° C., 10 min) and the supernatant is removed. The pellet isresuspended (20% w/v) and the suspension is centrifuged (1000×g, 4° C.,10 min). The two supernatants are combined and centrifuged (15 000×g, 4°C., 30 min). The pellet obtained in this way is referred to as the P2fraction.

The P2 pellet is washed with binding buffer (50 mM Tris-HCl, 1 mM MgCl₂,120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, pH 7.4), and centrifuged (15 000×g,4° C., 30 min), twice.

The P2 membranes are resuspended in binding buffer and incubated in avolume of 250 μl (amount of membrane protein 0.1-0.5 mg) in the presenceof 1-5 nM [³H]-methyllycaconitine, 0.1% (w/v) BSA (bovine serum albumin)and various concentrations of the test substance at 21° C. for 2.5 h.Incubation is then carried out in the presence of 1 μM α-bungarotoxin or100 μM nicotine or 10 μM MLA (methyllycaconitine) to determine thenon-specific binding.

The incubation is stopped by adding 4 ml PBS (20 mM Na₂HPO₄, 5 mMKH₂PO₄, 150 mM NaCl, pH 7.4, 4° C.) and filtering through type A/E glassfibre filters (Gelman Sciences) which have previously been placed in0.3% (v/v) polyethyleneimine (PEI) for 3 h. The filters are washed twicewith 4 ml of PBS (4° C.), and the bound radioactivity is determined byscintillation measurement. All the assays are carried out in triplicate.The dissociation constant of the test substance K_(i) was determinedfrom the IC₅₀ of the compounds (concentration of the test substance atwhich 50% of the ligand bound to the receptor is displaced), thedissociation constant K_(D) and the concentration L of[³H]-methyllycaconitine using the equation K_(i)=IC₅₀/(1+L/K_(D)).

In place of [³H]-methyllycaconitine it is also possible to employ otherα7-nAChR-selective radioligands such as, for example,[¹²⁵I]-α-bungarotoxin or nonselective nAChR radioligands together withinhibitors of other nAChRs.

Representative in vitro data for the effects of the compounds of theinvention are shown in Table A: TABLE A Example K_(i) (nM) 19 42.0 353.7 36 63.0 37 80.0 42 37.0 46 58.0 48 75.0 51 3.9 58 3.1 59 20.0 6250.0 64 20.0 65 55.0 68 2.0 73 2.8 74 22.0 76 6.7 77 20.0 78 80.0 8031.0 88 28.0

The suitably of the compounds of the invention for the treatment ofcognitive impairments can be shown in the following animal models:

2. Object Recognition Test

The object recognition test is a memory test. It measures the ability ofrats (and mice) to distinguish between familiar and unfamiliar objects.

The test is carried out as described by Blokland et al., NeuroReport1998, 9, 4205-4208; A. Ennaceur J. Delacour, Behav. Brain Res. 1988, 31,47-59; A. Ennaceur K. Meliani, Psychopharmacology 1992, 109, 321-330;and Prickaerts et al., Eur. J. Pharmacol. 1997, 337, 125-136.

In a first run, a rat is confronted in an otherwise empty observationarena of relatively large size by two identical objects. The rat willinvestigate, i.e. sniff round and touch, both objects extensively. In asecond run, after an interval of 24 hours, the rat is put in theobservation arena again. One of the familiar objects has now beenreplaced by a new, unfamiliar object. If a rat recognizes the familiarobject, it will concentrate on investigating the unfamiliar object.However, after 24 hours, a rat has normally forgotten which object itinvestigated in the first run, and it will therefore inspect bothobjects to the same extent. Administration of a substance with alearning- and memory-improving effect may lead to a rat recognizing theobject seen in the first run 24 hours previously as familiar. It willinvestigate the new, unfamiliar object in more detail than the familiarone. This memory ability is expressed in a discrimination index. Adiscrimination index of zero means that the rat investigates bothobjects, the old and the new, for equal times; that is to say it has notrecognized the old object and reacts to both objects as if they were newand unfamiliar. A discrimination index greater than zero means that therat inspects the new object for longer than the old one; that is to saythe rat has recognized the old object.

3. Social Recognition Test:

The social recognition test is a test to examine the learning- ormemory-improving effect of test substances.

Adult rats housed in groups are placed singly in test cages 30 minutesbefore the start of the test. Four minutes before the start of the test,the test animal is put in an observation box. After this adaptationtime, a juvenile animal is put in with the test animal and the time forwhich the adult animal investigates the juvenile animal is measured for2 minutes (trial 1). All behaviours clearly directed at the young animalare measured, i.e. anogenital inspection, pursuit and fur care, duringwhich the old animal is no further than 1 cm from the young animal. Thejuvenile animal is then taken out, and the adult is left in its testcage (for 24-hour retention, the animal is returned to its home cage).The adult test animal is treated with test substance before or after thefirst test. Depending on the timing of the treatment, the learning orthe storage of the information about the young animal can be influencedby the substance. After a fixed period (retention), the test is repeated(trial 2). A larger difference between the investigation times measuredin trials 1 and 2 means that the adult animal has remembered the younganimal better.

The compounds of the formula (I) according to the invention are suitablefor use as medicaments for humans and animals.

The present invention also includes pharmaceutical preparations which,besides inert, nontoxic, pharmaceutically suitable excipients andcarriers, contain one or more compounds of the formula (I), or whichconsist of one or more compounds of the formula (1), and processes forproducing these preparations.

The compounds of the formula (I) are to be present in these preparationsin a concentration of from 0.1 to 99.5% by weight, preferably from 0.5to 95% by weight, of the complete mixture.

Besides the compounds of the formula (I), the pharmaceuticalpreparations may also contain other active pharmaceutical ingredients.

The abovementioned pharmaceutical preparations can be produced by knownmethods in a conventional way using, for example, the auxiliary orauxiliaries or excipient(s).

The novel active ingredients can be converted in a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable excipients or solvents. Inthese cases, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of the entiremixture, i.e. in amounts which are sufficient to reach the stated doserange.

The formulations are produced for example by extending the activeingredients with solvents and/or excipients, where appropriate with useof emulsifiers and/or dispersants, it being possible for example whenwater is used as diluent where appropriate to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight or of themode of administration, of the individual behaviour toward themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered, it may be advisable to divide theseinto a plurality of single doses over the day.

Abbreviations:

-   BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl-   DCI direct chemical ionization (in MS)-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   EDC N′-(3-Dimethylaminopropyl)-N-ethylcarbodiimide×HCl-   EDTA Ethylenediaminetetraacetic acid-   eq. Equivalent(s)-   ESI Electrospray ionization (in MS)-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-Hydroxy-1H-benzotriazole×H₂O-   HPLC High pressure/high performance liquid chromatography-   LC-MS Liquid chromatography with coupled mass spectroscopy-   MS Mass spectroscopy-   NMR Nuclear magnetic resonance spectroscopy-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   RT Room temperature, 20° C.-   R_(t) Retention time (in HPLC)-   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   Tris Tris(hydroxymethyl)aminomethane

LC-MS method A: MS instrument: Micromass Quattro LCZ Ionization: ESIpositive HPLC instrument: HP 1100 UV detector DAD: 208-400 nm Oventemperature: 40° C. Column: Symmetry C 18 50 mm × 2.1 mm; 3.5 μm Flowrate Gradient: Time (min) A: % B: % (ml/min) 0.00 10.0 90.0 0.50 4.0090.0 10.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.00.50A: Acetonitrile + 0.1% formic acidB: Water + 0.1% formic acid

LC-MS method B: MS instrument: Finnigan MAT 900S Ionization: ESIpositive HPLC instrument: TSP: P4000, AS3000, UV3000HR UV detector3000HR: 210 nm Oven temperature: 70° C. Column: Symmetry C 18 150 mm ×2.1 mm; 5 μm Supplier: Waters Flow rate Gradient: Time (min) A: % B: %C: % (ml/min) 0 2 49 49 0.9 2.5 95 2.5 2.5 1.2 5 95 2.5 2.5 1.2 5.5 2 4949 1.2 6.5 2 49 49 1.2 7 2 49 49 0.9A: AcetonitrileB: Water + 0.6 g/l 35% strength hydrochloric acidC: Water

LC-MS method C: MS instrument: Micromass Platform LCZ Ionization: ESIpositive HPLC instrument: HP 1100 UV detector DAD: 208-400 nm Oventemperature: 40° C. Column: Symmetry C 18 50 mm × 2.1 mm; 3.5 μm Flowrate Gradient: Time (min) A: % B: % (ml/min) 0.00 10.0 90.0 0.50 4.0090.0 10.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.00.50A: Acetonitrile + 0.1% formic acidB: Water + 0.1% formic acidLC-MS method D:

Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; Mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+0.05% formic acid; Gradient: 0.0 min 90% A→4.0 min 10%A→6.0 min 10% A; Oven: 40° C.; Flow rate: 0.5 mmin; UV detection:208-400 nm.

LC-MS method E:

Instrument: Micromass Quattro LCZ, HP1100; Column: Uptisphere HDO, 50mm×2.0 mm, 3 μm; Mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+0.05% formic acid; Gradient: 0.0 min 100% A→0.2 min 100%A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; Oven: 55° C.; Flow rate:0.8 ml/min; UV detection: 208-400 nm.

LC-MS Method F:

Instrument: Micromass Quattro LCZ, HP1100; Column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; Mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+0.05% formic acid; Gradient: 0.0 min 90% A→4.0 min 10%A→6.0 min 10% A; Oven: 40° C.; Flow rate: 0.5 ml/min; UV detection:208-400 nm.

LC-MS method G:

MS instrument: Micromass ZQ; HPLC instrument: Waters Alliance 2790;Column: Uptisphere C18, 50 mm×2.0 mm, 3.0 μm; Mobile phase A:acetonitrile+0.05% formic acid, mobile phase B: water+0.05% formic acid;Gradient: 0.0 min 5% A→2.0 min 40% A→4.5 min 90% A→5.5 min 90% A; Oven:45° C.; Flow rate: 0.0 min 0.75 ml/min→4.5 min 0.75 ml/min→5.5 min 1.25ml/min; UV detection: 210 nm.

HPLC method H:

Instrument: HP1100 with DAD detection; column: Kromasil RP-18, 60 mm×2mm, 3.5 μm; mobile phase A: 5 ml HClO₄/l H₂O, mobile phase B:acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min90% B; Flow rate: 0.75 ml/min; Temperature: 30° C.; UV detection: 210nm.

Starting Materials:

General reaction scheme for the synthesis of methyl1-benzothiophene-2-carboxylates:

General Procedure for the Synthesis of methyl1-benzothiophene-2-carboxylates

Under an argon atmosphere, 1.5 equivalents of sodium hydride (60% pure)are initially charged in absolute DMSO (0.60-1.26 M suspension). At roomtemperature, 1.1 equivalents of methyl mercaptoacetate are slowly addeddropwise to the reaction mixture, and it is left to stir at roomtemperature until evolution of hydrogen ceases (about 15 min). 1.0equivalents of the appropriate benzaldehyde are dissolved in absoluteDMSO (1.60-3.36 M solution) and added at room temperature to thereaction mixture. The reaction mixture is stirred until the reaction iscomplete (about 5-10 min) and then poured into ice-water. The resultingprecipitate is filtered off with suction, dried at 40° C. under reducedpressure overnight and reacted further as crude product.

General Reaction Scheme for the Synthesis of1-benzothiophene-2-carboxylic acids

General Procedure for the Synthesis of 1-benzothiophene-2-carboxylicacids

A mixture of equal parts of THF and 2 N potassium hydroxide solution(0.28-0.47 M solution) is added to the appropriate methyl1-benzothiophene-2-carboxylate. The reaction mixture is left to stir atroom temperature overnight. The THF is removed under reduced pressureand the aqueous reaction mixture is acidified with concentratedhydrochloric acid. The resulting precipitate is filtered off withsuction and dried under reduced pressure at 40° C.

General Procedure for Amide Linkage Between 3-guinuclidinamine and2-benzothiophene- or 2-benzofurancarboxylic acids (variant A)

1.5 eq. of the appropriate enantiomeric 3-quinuclidinamine hydrochlorideare, together with 1 eq. of the carboxylic acid and 1.5 eq. of HATU,initially charged in DMF at 0° C. After addition of 1.5 eq. ofN,N-diisopropylethylamine, the mixture is stirred for 30 min. A further4 eq. of N,N-diisopropylethylamine are added, and the mixture is stirredat RT overnight. Purification is carried out chromatographically.

General Procedure for Amide Linkage Between 3-guinuclidinamine and2-benzothiophene- or 2-benzofurancarboxylic acids (variant B)

1.0 eq. of the appropriate enantiomeric 3-quinuclidinaminedihydrochloride are, together with 1 eq. of the carboxylic acid and 1.2eq. of HATU, initially charged in DMF at 0° C. After addition of 1.2 eq.of N,N-diisopropylethylamine, the mixture is stirred for 30 min. Afurther 2.4 eq. of N,N-diisopropylethylamine are added, and the mixtureis stirred at RT overnight. Purification is carried outchromatographically.

General Procedure for the Synthesis of methyl3-aminothienopyridine-2-carboxylates

1.0 equivalents of the appropriate pyridine derivative are dissolved inabsolute DMSO (0.93-0.96 M solution), and 2 equivalents of triethylamineare added. After addition of 1 equivalent of methyl mercaptoacetate, thereaction mixture is stirred at 60° C. overnight. The reaction mixture ispoured into ice-water and stirred therein. The precipitated solid isfiltered off with suction and, if required, purified by columnchromatography (silica gel 60, mobile phase toluene/ethyl acetate 20:1to 5:1).

General Procedure for the Synthesis of methylthienopyridine-2-carboxylates

With cooling at −5° C., 1.0 equivalents of the appropriate methyl3-aminothienopyridine-2-carboxylate is initially charged in 75% strengthsulfuric acid (0.33-0.36 M solution). A solution of 3.2 equivalents ofsodium nitrite in water (0.92-1.00 M solution) is slowly added dropwiseto the reaction mixture such that the temperature of the reactionmixture does not exceed 0° C. The mixture is stirred at 0° C. for 45min. 60-65 equivalents of ice-cold 50% strength hypophosphoric acid arethen added dropwise to the reaction mixture, again in such a way thatthe temperature does not exceed 0° C. The reaction mixture is stirred at−5° C. for one hour and then kept in the fridge overnight. The reactionmixture is diluted with sodium bicarbonate solution and ethyl acetate,and sodium bicarbonate is added a little at a time until the mixturegives a basic reaction. Work-up is described in the examples below.

General Procedure for the Synthesis of thienopyridine-2-carboxylic acids

A mixture of equal parts of THF and 2 N potassium hydroxide solution(0.22 M solution) is added to the appropriate methylthienopyridine-2-carboxylate. The reaction mixture is stirred at roomtemperature overnight. The reaction mixture is diluted with water,washed twice with ethyl acetate and acidified with concentratedhydrochloric acid. Work-up is described in the examples below.

EXAMPLE 1A Methyl 6-fluoro-1-benzothiophene-2-carboxylate

Using 2.00 g (14.07 mmol) of 2,4-difluorobenzaldehyde, 0.84 g (21.11mmol) of sodium hydride (60% pure) and 1.64 g (15.48 mmol) of methylmercaptoacetate, 1.99 g of the desired product are obtained. The productis obtained in a purity which permits further reaction and is reactedwithout further purification.

MS (EIpos): m/z=210 (M)⁺.

EXAMPLE 2A Methyl 5-bromo-1-benzothiophene-2-carboxylate

1.62 g (8.00 mmol) of 5-bromo-2-fluorobenzaldehyde, 0.48 g (12.00 mmol)of sodium hydride (60% pure) and 0.93 g (8.80 nmmol) of methylmercaptoacetate give 1.53 g (71% of theory) of the desired product.

LC-MS (Method A): R_(t)=4.80 min.

MS (EIpos): m/z=272 (M)⁺

¹H NMR (200 MHz, CDCl₃): δ=8.07-7.92 (m, 2H), 7.78-7.66 (m, 1H),7.59-7.48 (m, 1H), 3.95 (s, 3H).

EXAMPLE 3A Methyl 5-methyl-1-benzothiophene-2-carboxylate

2.32 g (16.78 mmol) of 2-fluoro-5-methylbenzaldehyde, 1.01 g (25.17mmol) of sodium hydride (60% pure) and 1.96 g (18.46 mmol) of methylmercaptoacetate give 1.96 g (57% of theory) of the desired product.

LC-MS (Method C): R_(t)=4.68 min.

MS (EIpos): m/z=206 (M)⁺

¹H NMR (200 MHz, CDCl₃): δ=7.99 (s, 1H), 7.79-7.64 (m, 2H), 7.34-7.23(m, 1H), 3.94 (s, 3H).

EXAMPLE 4A 6-Fluoro-1-benzothiophene-2-carboxylic acid

1.99 g (9.46 mmol) of methyl 6-fluoro-1-benzothiophene-2-carboxylategive 1.43 g of the desired product. The product is obtained in a puritywhich permits further reaction and is reacted without furtherpurification.

MS (EIpos): m/z=196 (M)⁺.

EXAMPLE 5A 5-Bromo-1-benzothiophene-2-carboxylic acid

1.53 g (5.64 mmol) of methyl 5-bromo-1-benzothiophene-2-carboxylate give1.31 g (90% of theory) of the desired product.

HPLC (Method H): R_(t)=4.50 min.

MS (ESIneg): m/z=255 (M−H)⁻

¹H NMR (200 MHz, CDCl₃): δ=8.01 (d, 1H), 7.94 (s, 1H), 7.74 (d, 1H),7.53 (dd, 1H).

EXAMPLE 6A 5-Methyl-1-benzothiophene-2-carboxylic acid

1.96 g (9.49 mmol) of methyl 5-methyl-1-benzothiophene-2-carboxylategive 1.46 g (80% of theory) of the desired product.

HPLC (Method H): R_(t)=4.38 min.

MS (DCI): m/z=210 (M+NH₄)⁺

¹H NMR (200 MHz, CDCl₃): δ=8.09 (s, 1H), 7.65-7.83 (m, 2H), 7.39-7.29(m, 1H), 2.49 (s, 3H).

EXAMPLE 7A Methyl 3-aminothieno[2,3-b]pyridine-2-carboxylate

0.92 g (6.51 mmol) of 2-chloronicotinonitrile, 1.37 g (13.53 mmol) oftriethylamine and 0.72 g (6.77 mmol) of methyl mercaptoacetate give 0.22g (16% of theory) of the desired product.

HPLC (Method H): R_(t)=3.56 min.

MS (ESIpos): m/z=209 (M+H)⁺

¹H NMR (300 MHz, CDCl₃): δ=8.76-8.62 (m, 1H), 7.99-7.87 (m, 1H),7.37-7.28 (m, 1H), 5.91 (br. s, 2H), 3.91 (s, 3H).

EXAMPLE 8A Methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate

2.00 g (14.43 mmol) of 2-chloro-2-pyridinecarbonitrile, 3.03 g (30.02mmol) of triethylamine and 1.59 g (15.01 mmol) of methyl mercaptoacetategive 2.47 g (81% of theory) of the desired product.

LC-MS (Method A): R_(t)=3.4 min.

MS (ESIpos): m/z=209 (M+H)⁺

¹H NMR (300 MHz, CDCl₃): δ=8.67-8.58 (m, 1H), 8.10-8.01 (m, 1H),7.42-7.33 (m, 1H), 6.22 (br. s, 2H), 3.92 (s, 3H).

EXAMPLE 9A Methyl thieno[2,3-b]pyridine-2-carboxylate

The synthesis is carried out according to the general procedure; forwork-up, the resulting precipitate is filtered off with suction andwashed twice with water and three times with ethyl acetate. The organicphase of the resulting filtrate is separated off, dried andconcentrated. Using 0.22 g (1.07 mmol) of methyl3-aminothieno[2,3-b]pyridine-2-carboxylate and 0.24 g (3.41 mmol) ofsodium nitrite, 84 mg (41% of theory) of the desired product areobtained.

LC-MS (Method A): R_(t)=3.34 min.

MS (ESIpos): m/z=194 (M+H)⁺

¹H NMR (200 MHz, CDCl₃): δ=8.82-8.66 (m, 1H), 8.53-8.38 (m, 1H), 8.23(s, 1H), 7.63-7.48 (m, 1H), 3.92 (s, 3H).

EXAMPLE 10A Methyl thieno[3,2-b]pyridine-2-carboxylate

The synthesis is carried out according to the general procedure; forwork-up, the resulting precipitate is filtered off with suction andwashed repeatedly with water, ethyl acetate and THF. The organic phasesof the resulting filtrates are separated off, the aqueous phase iswashed with ethyl acetate and the combined organic phases are dried andconcentrated. The resulting product is purified by preparative

HPLC. Using 2.40 g (11.53 mmol) of methyl3-aminothieno[3,2-b]pyridine-2-carboxylate and 2.54 g (36.88 mmol) ofsodium nitrite, 0.12 g (5% of theory) of the desired product areobtained.

LC-MS (Method C): R_(t)=3.18 min.

MS (ESIpos): m/z=194 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ=8.83-8.76 (m, 1H), 8.63-8.56 (m, 1H), 8.21(s, 1H), 7.58-7.50 (m, 1H), 3.93 (s, 3H).

EXAMPLE 11A Thieno[2,3-b]pyridine-2-carboxylic acid

The synthesis is carried out according to the general procedure; forwork-up, the aqueous phase is extracted twice with ethyl acetate, thecombined organic phases are washed with saturated sodium chloridesolution and the solvent is removed under reduced pressure. Using 84 mg(0.43 mmol) of methyl thieno[2,3-b]pyridine-2-carboxylate, 49 mg (63% oftheory) of the desired product are obtained.

LC-MS (Method C): R_(t)=2.46 min.

MS (ESIpos): m/z=180 (M+H)⁺

¹H NMR (200 MHz, CDCl₃): δ=13.76 (br. s, 1H), 8.80-8.63 (m, 1H),8.50-8.34 (m, 1H), 8.11 (s, 1H), 7.61-7.47 (m, 1H).

EXAMPLE 12A Thieno[3,2-b]pyridine-2-carboxylic acid

The synthesis is carried out according to the general procedure; forwork-up, the precipitated solid is filtered off with suction, washedwith water and acetonitrile and dried under reduced pressure. Using 115mg (0.60 mmol) of methyl thieno[3,2-b]pyridine-2-carboxylate, 77 mg (72%of theory) of the desired product are obtained.

HPLC (Method H): R_(t)=2.08 min.

MS (ESIpos): m/z=180 (M+H)⁺

¹H NMR (400 MHz, D₂O): δ=8.63 (d, 1H), 8.39 (d, 1H), 7.85 (s, 1H), 7.45(dd, 1H).

EXAMPLE 13A Methyl 7-bromo-1-benzothiophene-2-carboxylate

Using 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde, 8.2 g (205.7mmol) of sodium hydride (60% pure) and 16.0 g (150.9 mmol) of methylmercaptoacetate, 20.57 g of a mixture of the title compound and thecorresponding acid (about 1:1) are obtained.

EXAMPLE 14A Methyl thieno[2,3-f][1,3]benzodioxole-6-carboxylate

Using 3.0 g (13.1 mmol) of 6-bromopiperonal, 0.79 g (19.7 mmol) ofsodium hydride (60% pure) and 1.53 g (14.4 mmol) of methylmercaptoacetate, 732 mg (18.5% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.03 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H),6.14 (s, 2H), 3.86 (s, 3H) ppm.

HPLC: R_(t)=4.6 min (Method H)

MS (ESIpos): m/z=237 (M+H)⁺

EXAMPLE 15A Methyl 6-cyano-1-benzothiophene-2-carboxylate

4.08 g (23.2 mmol) of 4-cyano-2-nitrobenzaldehyde, 2.46 g (23.2 mmol) ofmethyl mercaptoacetate and 6.46 ml (46.4 mmol) of triethylamine in 12.3ml of DMSO are heated at 80° C. for 2.5 h. The reaction solution ispoured into 400 ml of ice-water. After addition of 4 ml of acetic acid,the resulting precipitate is filtered off with suction, washed twicewith water and dried at 50° C. under reduced pressure overnight. Thisgives 4.19 g (83.2% of theory) of the title compound.

¹H NMR (200 MHz, DMSO-d₆): δ=8.73 (d, 1H), 8.32 (s, 1H), 8.21 (d, 1H),7.85 (dd, 1H), 3.92 (s, 3H) ppm.

HPLC: R_(t)=4.4 min (Method H)

MS (ESIpos): m/z=218 (M+H)⁺

EXAMPLE 16A Methyl 7-fluoro-1-benzothiophene-2-carboxylate

5.0 g (35.2 mmol) of 2,3-difluorobenzaldehyde, 2.11 g (52.8 mmol) ofsodium hydride (60% pure) and 4.11 g (38.7 mmol) of methylmercaptoacetate give 3.30 g (44.6% of theory) of the title compound.

¹H NMR (400 MHz, DMSO-d6): δ=8.33 (d, 1H), 7.92 (d, 1H), 7.55 (m, 1H),7.46 (dd, 1H), 3.93 (s, 3H) ppm.

HPLC: R_(t)=4.7 min (Method H)

MS (ESIpos): m/z=228 (M+NH₄)⁺

EXAMPLE 17A Methyl 7-methoxy-1-benzothiophene-2-carboxylate

550 mg (3.97 mmol) of potassium carbonate and 350 mg (3.31 mmol) ofmethyl mercaptoacetate are added to a solution of 600 mg (3.31 mmol) of3-methoxy-2-nitrobenzaldehyde in 8 ml of DMF. The reaction mixture isheated at 70° C. for 4 h. After cooling, water is added. The resultingprecipitate is filtered off, washed with water and dried under reducedpressure. This gives 387 mg (45.7% of theory) of the title compound.

¹H NMR (200 MHz, DMSO-d₆): δ=8.21 (s, 1H), 7.63 (d, 1H), 7.46 (dd, 1H),7.11 (d, 1H), 3.98 (s, 3H), 3.89 (s, 3H) ppm.

MS (ESIpos): m/z=240 (M+NH₄)⁺

EXAMPLE 18A Methyl 6-nitro-1-benzothiophene-2-carboxylate

24.8 g (126.7 mmol) of 2,4-dinitrobenzaldehyde, 13.4 g (126.7 mmol) ofmethyl mercaptoacetate and 35.3 ml (253.3 mmol) of triethylamine in 74.5ml of DMSO are heated at 80° C. for 1 h. The reaction solution is pouredinto 250 ml of ice-water. The resulting precipitate is filtered off withsuction, washed with water and dried at 50° C. under reduced pressureovernight. This gives 16.1 g (53.6% of theory) of the title compound.

¹H NMR (300 MHz, CDCl₃): δ=8.80 (d, 1H), 8.26 (dd, 1H), 8.12 (s, 1H),8.00 (d, 1H), 3.99 (s, 3H) ppm.

HPLC: R_(t)=4.7 min (Method H)

MS (ESIpos): m/z=255 (M+NH₄)⁺

EXAMPLE 19A Methyl 4-nitro-1-benzothiophene-2-carboxylate

1.0 g (5.10 mmol) of 2,6-dinitrobenzaldehyde, 0.54 g (5.10 mmol) ofmethyl mercaptoacetate and 1.42 ml (10.20 mmol) of triethylamine in 3 mlof DMSO are heated at 80° C. for 3.5 h. The reaction solution is pouredinto 100 ml of ice-water. The resulting precipitate is filtered off withsuction, washed with water and dried at 50° C. under reduced pressureovernight. This gives 1.10 g (88.7% of theory) of the title compound.

¹H NMR (200 MHz, DMSO-d₆): δ=8.63 (s, 1H), 8.61 (d, 1H), 8.45 (d, 1H),7.80 (dd, 1H), 3.97 (s, 3H) ppm.

HPLC: R_(t)=4.6 min (Method H)

MS (ESIpos): m/z=238 (M+NH₄)⁺

EXAMPLE 20A Methyl 6-bromo-1-benzothiophene-2-carboxylate

Using 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde, 1.93 g (48.3mmol) of sodium hydride (60% pure) and 3.76 g (35.5 mmol) of methylmercaptoacetate, 4.06 g (46.4% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H),7.65 (dd, 1H), 3.90 (s, 3H) ppm.

HPLC: R_(t)=5.3 min (Method H)

MS (ESIpos): m/z=270 (M+), 288 (M+NH₄)⁺

EXAMPLE 21A Methyl 7-trifluoromethyl-1-benzothiophene-2-carboxylate

Using 5.0 g (26.0 mmol) of 2-fluoro-3-trifluoromethylbenzaldehyde, 1.56g (39.0 mmol) of sodium hydride (60% pure) and 3.0 g (28.6 mmol) ofmethyl mercaptoacetate, 5.4 g (79.7% of theory) of the title compoundare obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.40 (s, 1H), 8.38 (m, 1H), 8.00 (d, 1H),7.73 (dd, 1H), 3.92 (s, 3H) ppm.

HPLC: R_(t)=5.1 min (Method H)

MS (ESIpos): m/z=260 (M⁺)

EXAMPLE 22A Methyl 5-trifluoromethyl-1-benzothiophene-2-carboxylate

Using 4.28 g (22.3 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde, 1.34g (33.4 mmol) of sodium hydride (60% pure) and 2.6 g (24.5 mmol) ofmethyl mercaptoacetate, 4.93 g (80.0% of theory) of the title compoundare obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.48 (s, 1H), 8.37 (s, 1H), 8.33 (d, 1H),7.82 (m, 1H), 3.93 (s, 3H) ppm.

MS (ESIpos): m/z=260 (M⁺)

EXAMPLE 23A Methyl 7-chloro-1-benzothiophene-2-carboxylate

Using 1.0 g (6.31 mmol) of 2-fluoro-3-chlorobenzaldehyde, 0.38 g (9.46mmol) of sodium hydride (60% pure) and 0.74 g (6.94 mmol) of methylmercaptoacetate, 1.04 g (72.3% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.34 (s, 1H), 8.06 (dd, 1H), 7.70 (dd, 1H),7.56 (dd, 1H), 3.92 (s, 3H) ppm.

HPLC: R_(t)=4.9 min (Method H)

MS (ESIpos): m/z=227 (M+H)⁺

EXAMPLE 24A Methyl 5-fluoro-1-benzothiophene-2-carboxylate

Using 5.0 g (35.2 mmol) of 2,5-difluorobenzaldehyde, 2.11 g (52.78 mmol)of sodium hydride (60% pure) and 4.11 g (38.7 mmol) of methylmercaptoacetate, 1.1 g (14.3% of theory) of the title compound areobtained.

¹H NMR (200 MHz, CDCl₃): δ=8.02 (s, 1H), 7.82 (dd, 1H), 7.53 (dd, 1H),7.23 (ddd, 1H), 3.96 (s, 3H) ppm.

HPLC: R_(t)=4.8 min (Method H)

MS (ESIpos): m/z=210 (M⁺)

EXAMPLE 25A Methyl 4-fluoro-1-benzothiophene-2-carboxylate

Using 5.0 g (35.2 mmol) of 2,6-difluorobenzaldehyde, 2.11 g (52.8 mmol)of sodium hydride (60% pure) and 4.11 g (38.7 mmol) of methylmercaptoacetate, 5.61 g (72.8% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.16 (s, 1H), 7.95 (d, 1H), 7.59 (ddd, 1H),7.32 (dd, 1H), 3.91 (s, 3H) ppm.

MS (ESIpos): m/z=210 (M⁺)

EXAMPLE 26A Methyl 5,7-difluoro-1-benzothiophene-2-carboxylate

Using 3.94 g (24.6 mmol) of 2,3,5-trifluorobenzaldehyde, 1.48 g (36.9mmol) of sodium hydride (60% pure) and 2.88 g (27.1 mmol) of methylmercaptoacetate, 3.58 g (56% of theory) of the title compound areobtained in a purity of 89%. Recrystallization from methanol gives theproduct in a purity of 97%.

¹H NMR (200 MHz, DMSO-d₆): δ=8.28 (d, 1H), 7.81 (dd, 1H), 7.61 (m, 1H),3.93 (s, 3H) ppm.

MS (ESIpos): m/z=228 (M⁺)

EXAMPLE 27A Methyl 6-methoxy-1-benzothiophene-2-carboxylate

Using 2.5 g (16.2 mmol) of 2-fluoro-4-methoxybenzaldehyde, 0.97 g (24.3mmol) of sodium hydride (60% pure) and 1.89 g (17.8 mmol) of methylmercaptoacetate, 3.05 g (84.7% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=8.12 (s, 1H), 7.91 (d, 1H), 7.64 (d, 1H),7.09 (dd, 1H), 3.88 (s, 3H), 3.87 (s, 3H) ppm.

HPLC: R_(t)=4.7 min (Method H)

MS (ESIpos): m/z=223 (M+H)⁺, 240 (M+NH₄)⁺

EXAMPLE 28A Methyl 6-cyano-1-benzothiophene-2-carboxylate

2.5 g (15.1 mmol) of 2-chloro-3-cyanobenzaldehyde are reacted accordingto the general procedure with 0.90 g (22.7 mmol) of sodium hydride (60%pure) and 1.76 g (16.6 mmol) of methyl mercaptoacetate. The resultingreaction product is initially purified by silica gel columnchromatography (mobile phase: dichloromethane/methanol 100:1) and thendissolved in 30 ml of pyridine, and 650 μl (8.4 mmol) of methanesulfonylchloride are added. The mixture is stirred at 80° C. for 2 h. Aftercooling, ethyl acetate is added and the mixture is washed twice with 1Nhydrochloric acid and once with saturated sodium chloride solution,dried over sodium sulfate, concentrated and dried under high vacuum.This gives 1.63 g (49.9% of theory) of the title compound.

¹H NMR (400 MHz, DMSO-d₆): δ=8.40 (d, 1H), 8.39 (s, 1H), 8.16 (d, 1H),7.70 (dd, 1H), 3.94 (s, 3H) ppm.

HPLC: R_(t)=4.3 min (Method H)

MS (ESIpos): m/z=218 (M+H⁺)

EXAMPLE 29A (2-Chloro-3-nitrophenyl)methanol

10.0 g (49.61 mmol) of 2-chloro-3-nitrobenzoic acid are initiallycharged in 50 ml of THF. With ice cooling, 104 ml of 1M borane/THFcomplex are added, and the mixture is stirred at RT overnight. At 0° C.,the mixture is carefully hydrolyzed using water. After the evolution ofgas has ceased, the mixture is diluted with 500 ml of water and theaqueous phase is extracted three times with in total 500 ml of ethylacetate. The organic phase is washed with saturated sodium chloridesolution and dried over magnesium sulfate. The solvent is then removedunder reduced pressure using a rotary evaporator. This gives 9.20 g (98%of theory) of the title compound.

¹H NMR (300 MHz, DMSO-d6): δ=7.89 (m, 2H), 7.62 (t, 1H), 5.70 (t, 1H),4.67 (d, 2H).

HPLC: R_(t)=3.53 min (Method H)

MS (ESIpos): m/z=205 (M+NH₄)⁺

EXAMPLE 30A 2-Chloro-3-nitrobenzaldehyde

9.2 g (49.05 mmol) of (2-chloro-3-nitrophenyl)methanol and 13.2 g (151.8mmol) of activated manganese(IV) oxide in 50 ml of chloroform are heatedunder reflux for 20 h. The mixture is filtered through kieselguhr,concentrated and dried under high vacuum. The resulting title compoundis directly reacted further.

¹H NMR (200 MHz, DMSO-d₆): δ=10.34 (s, 1H), 8.32 (dd, 1H), 8.14 (dd,1H), 7.79 (t, 1H) ppm.

HPLC: R_(t)=3.76 min (Method H)

MS (ESIpos): m/z=185 (M)⁺

EXAMPLE 31A Methyl 7-nitro-1-benzothiophene-2-carboxylate

Using 3.04 g (16.4 mmol) of 2-chloro-3-nitrobenzaldehyde, 0.98 g (24.6mmol) of sodium hydride (60% pure) and 2.09 g (19.7 mmol) of methylmercaptoacetate, 3.68 g (85% of theory) of the title compound areobtained.

¹H NMR (300 MHz, DMSO-d₆): δ=8.60 (dd, 1H), 8.53 (dd, 1H), 8.44 (s, 1H),7.80 (dd, 1H), 3.95 (s, 3H) ppm.

HPLC: R_(t)=4.6 min (Method H)

MS (ESIpos): m/z=255 (M+NH₄)⁺

EXAMPLE 32A 3-Bromo-2-hydroxybenzaldehyde

20 g (115.6 mmol) of 4-bromo-2-hydroxybenzaldehyde, together with 16.84g (176.9 mmol) of magnesium chloride, are initially charged in 500 ml ofanhydrous acetonitrile. 41.9 ml (300.6 mmol) of triethylamine are addedand the mixture is heated under reflux for 3 h. The mixture is cooled to0° C., and 300 ml of 2N hydrochloric acid are added. The aqueous phaseis extracted three times with a total of 600 ml of diethyl ether. Theorganic phase is washed with 200 ml of saturated sodium chloridesolution and then dried over magnesium sulfate. The solvent is removedunder reduced pressure. Any last solvent residues are finally removedunder high vacuum. 24 g (64% of theory) of the title compound areisolated and reacted further without further purification.

HPLC: R_(t)=4.25 min (Method H)

MS (ESIpos): m/z=201 (M)⁺

EXAMPLE 33A 7-Bromo-1-benzofuran-2-carboxylic acid

10 g (49.75 mmol) of 3-bromo-2-hydroxybenzaldehyde and 1.84 g (4.97mmol) of tetra-N-butylammonium iodide are, together with 27.5 g (199.0mmol) of anhydrous potassium carbonate, initially charged. 24.3 g(223.86 mmol) of methyl chloroacetate are added. The reaction mixture isheated at 130° C. for 4 h and then cooled to 0° C. using an ice bath.100 ml of THF and 16.75 g (298.5 mmol) of potassium hydroxide in 100 mlof water are added, the mixture is then stirred at 40° C. for 4 h. Thesolvent is removed under reduced pressure. The residue is diluted withwater and acidified with conc. hydrochloric acid. The product ispurified on silica gel 60 (mobile phase: toluene/ethyl acetate/aceticacid 40:10:1). The solvent is removed under reduced pressure. Any lastsolvent residues are finally removed under high vacuum. Finepurification is carried out by preparative

HPLC. 303 mg (2.5% of theory) of the title compound are isolated.

HPLC: R_(t)=4.16 min (Method H)

MS (ESIpos): m/z=258 (M+NH₄)⁺

EXAMPLE 34A 6-Bromo-1-benzofuran-2-carboxylic acid

8.0 g (39.8 mmol) of 4-bromo-2-hydroxybenzaldehyde and 1.47 g (3.98mmol) of tetra-N-butylammonium iodide are, together with 22 g (159.19mmol) of anhydrous potassium carbonate, initially charged. 9.07 g (83.57mmol) of methyl chloroacetate are added. The reaction mixture is heatedat 130° C. for 4 h and then cooled to 0° C. using an ice bath. 100 ml ofTHF and 13.4 g (238.8 mmol) of potassium hydroxide in 50 ml of water areadded and the mixture is then stirred at RT overnight. The solvent isremoved under reduced pressure. The residue is diluted with water andacidified with conc. hydrochloric acid. The product is filtered off anddried under high vacuum. For fine purification, the product is purifiedon silica gel 60 (mobile phase: toluene→toluene/acetic acid50:1→toluene/ethyl acetate/acetic acid 35:5:1). The solvent is removedunder reduced pressure. 3.8 g (40% of theory) of the title compound areisolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.91 (m, 1H), 7.61-7.51 (m, 3H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=258 (M+NH₄)⁺

EXAMPLE 35A 5,7-Difluoro-1-benzofuran-2-carboxylic acid

Step a):

1.0 g (7.69 mmol) of 2,4-difluorophenol is initially charged in 6 ml ofTFA. Over a period of 30 min, 2.16 g (15.37 mmol) ofhexamethylenetetramine are added a little at a time. The mixture is thenheated under reflux for 20 h. At RT, 9 ml of water and 4.5 ml of 50%strength sulfuric acid are added. After 2 h at RT, the reaction mixtureis extracted twice with in each case 30 ml of ethyl acetate. Thecombined organic phases are washed four times with 1N hydrochloric acidand once with water and then dried over magnesium sulfate. The crudeproduct is reacted further without further purification.

LC-MS (Method D): R_(t)=3.5 min.

MS (ESIneg): m/z=157 (M−H)⁻

Step b):

The crude product from the reaction above and 0.28 g (0.77 mmol) oftetra-N-butylammonium iodide are, together with 4.25 g (30.76 mmol) ofanhydrous potassium carbonate, initially charged. 1.75 g (16.15 mmol) ofmethyl chloroacetate are added. The reaction mixture is heated at 130°C. for 4 h and then cooled to 0° C. using an ice bath. 27 ml of THF,2.59 g (46.14 mmol) of potassium hydroxide and 27 ml of water are added.The mixture is stirred at RT overnight. The solvent is removed underreduced pressure. The residue is diluted with water and acidified withconc. hydrochloric acid. The mixture is extracted twice with ethylacetate. The combined organic phases are dried over magnesium sulfateand the solvent is removed under reduced pressure using a rotaryevaporator. The product is purified on silica gel 60 (mobile phase:toluene/ethyl acetate/acetic acid 35:5:1). The solvent is removed underreduced pressure. Any last solvent residues are finally removed underhigh vacuum. 235 mg (15% of theory over both steps) of the titlecompound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.57 (d, 1H), 7.25 (dd, 1H), 7.08 (dt,1H) ppm.

HPLC: R_(t)=3.91 min (Method H)

MS (ESIpos): m/z=216 (M+NH₄)⁺

EXAMPLE 36A 3-Bromo-5-fluoro-2-hydroxybenzaldehyde

1.0 g (5.24 mmol) of 2-bromo-4-fluorophenol is initially charged in 4 mlof TFA. Over a period of 20 min, 1.47 g (10.47 mmol) ofhexamethylenetetramine are added a little at a time. The mixture is thenheated under reflux for 28 h. At RT, 6 ml of water and 3 ml of 50%strength sulfuric acid are added. After 2 h at RT, the reaction mixtureis extracted twice with in each case 30 ml of ethyl acetate. Thecombined organic phases are washed four times with 1N hydrochloric acidand once with water and then dried over magnesium sulfate. The crudeproduct is reacted further without further purification.

¹H NMR (200 MHz, CDCl₃): δ=11.32 (s, 1H, br), 7.66-7.45 (m, 1H),7.32-7.21 (m, 1H) ppm.

LC-MS (Method D): R_(t)=4.2 min.

MS (ESIneg): m/z=217 (M−H)⁻

EXAMPLE 37A 7-Bromo-5-fluoro-1-benzofuran-2-carboxylic acid

Step a):

1.0 g (5.24 mmol) of 2-bromo-4-fluorophenol is initially charged in 4.0ml of trifluoroacetic acid. Over a period of 20 min, 1.47 g (10.47 mmol)of hexamethylenetetraamine are added a little at a time. The mixture isthen heated under reflux for 28 h. At RT, 6 ml of water and 3 ml of 50%strength sulfuric acid are added. After 2 h, the mixture is extractedtwice with in total 60 ml of ethyl acetate. The combined organic phasesare washed four times with 1N hydrochloric acid and once with water. Themixture is dried over magnesium sulfate and the solvent is removed underreduced pressure. Any last solvent residues are finally removed underhigh vacuum. The crude product is reacted further without furtherpurification.

Step b):

The crude product from the reaction above and 0.19 g (0.52 mmol) oftetra-N-butyl-ammonium iodide are, together with 2.9 g (20.96 mmol) ofanhydrous potassium carbonate, initially charged. 1.19 g (11.0 mmol) ofmethyl chloroacetate are added. The reaction mixture is heated at 130°C. for 4 h and then cooled to 0° C. using an ice bath. 18 ml of THF,1.76 g (31.44 mmol) of potassium hydroxide and 18 ml of water are added.The mixture is stirred at RT overnight. The solvent is removed underreduced pressure. The residue is diluted with water and acidified withconc. hydrochloric acid. The mixture is extracted twice with ethylacetate. The combined organic phases are dried over magnesium sulfateand the solvent is removed under reduced pressure using a rotaryevaporator. The product is purified on silica gel 60 (mobile phase:toluene/acetic acid 40:1). The solvent is removed under reducedpressure. Any last solvent residues are finally removed under highvacuum. 257 mg (19% of theory over both steps) of the title compound areisolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.60 (m, 1H), 7.48-7.35 (m, H).

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=276 (M+NH₄)⁺

EXAMPLE 38A 2-(Hydroxymethyl)-5-nitrophenol

10.0 g (54.6 mmol) of 4-nitrosalicylic acid are initially charged in 100ml of THF. With ice-cooling, 109 ml of 1 M borane/THF complex are added,and the mixture is stirred at RT overnight. The mixture is concentratedand the precipitate is filtered off with suction. The solid is dissolvedin ethyl acetate and dried over magnesium sulfate. After concentrationand drying under high vacuum, the title compound is directly reactedfurther.

MS (ESIpos): m/z=169 (M⁺)

EXAMPLE 39A 2-Hydroxy-4-nitrobenzaldehyde

6.0 g (35.5 mmol) of 2-(hydroxymethyl)-5-nitrophenol and 3.1 g (35.5mmol) of activated manganese (IV) oxide in 100 ml of chloroform areheated under reflux for 20 h. The mixture is filtered throughkieselguhr, concentrated and dried under high vacuum. The title compoundis directly reacted further.

MS (ESIpos): m/z=167 (M⁺)

EXAMPLE 40A 6-Nitro-1-benzofuran-2-carboxylic acid

5.8 g (34.7 mmol) of 2-hydroxy-4-nitrobenzaldehyde, 1.28 g (3.5 mmol) oftetra-N-butylammonium iodide and 19.2 g (138.8 mmol) of potassiumcarbonate are mixed, 7.9 g (72.9 mmol) of methyl chloroacetate are addedand the mixture is heated at 130° C. for 12 h. 100 ml of THF and, withice cooling, 11.7 g (208.2 mmol) of potassium hydroxide are added.Following the addition of 100 ml of water, the mixture is stirred at RTfor 20 h. Using concentrated hydrochloric acid, the pH is adjusted to 0.The mixture is extracted with ethyl acetate. The organic phase is washedwith water and dried over sodium sulfate. Following the addition ofsilica gel, the mixture is concentrated and chromatographed on silicagel (mobile phase gradient: toluene to toluene/methanol/glacial aceticacid 35:5:1). Concentration of the product fractions and drying underreduced pressure gives 1.31 g (18.2% of theory) of the title compound.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=225 (M+NH₄)⁺

EXAMPLE 41A 7-Nitro-1-benzofuran-2-carboxylic acid

3.0 g (17.9 mmol) of 2-hydroxy-5-nitrobenzaldehyde, 0.66 g (1.80 mmol)of tetra-N-butylammonium iodide and 9.92 g (71.81 mmol) of potassiumcarbonate are mixed, 4.09 g (37.7 mmol) of methyl chloroacetate areadded and the mixture is heated at 130° C. for 4 h. 35 ml of THF and,with ice cooling, 6.04 g (107.71 mmol) of potassium hydroxide are added.Following the addition of 50 ml of water, the mixture is stirred at RTfor 20 h. Using concentrated hydrochloric acid, the pH is adjusted to 0.The mixture is extracted with ethyl acetate. The organic phase is washedwith water and dried over sodium sulfate. After the addition of silicagel, the mixture is concentrated and chromatographed on silica gel(mobile phase gradient: toluene to toluene/methanol/glacial acetic acid35:5:1). Concentration of the product fractions and drying under reducedpressure gives 2.00 g (54% of theory) of the title compound.

¹H NMR (300 MHz, DMSO-d₆): δ=14.0 (s, 1H, br), 8.36 (d, 1H), 8.25 (d,1H), 7.88 (s, 1H), 7.59 (t, 1H) ppm.

HPLC: R_(t)=3.7 min (Method H)

LC-MS (Method G): R_(t)=2.52 min., m/z=208 (M+H)⁺

MS (ESIpos): m/z=208 (M+H)⁺

EXAMPLE 42A 6-[(tert-Butoxycarbonyl)amino]-1-benzothiophene-2-carboxylicacid

200 mg (1.04 mmol) of 6-amino-1-benzothiophene-2-carboxylic acid areadded to 2.5 ml (2.59 mmol) of a 1M solution, cooled to 0° C., of sodiumhexamethyldisilazane in tetrahydrofuran. The mixture is stirred at RTfor 15 minutes. 271.1 mg (1.24 mmol) of di-tert-butyl pyrocarbonate(Boc₂O) are added. The mixture is stirred at RT for 2 h, the contents ofthe flask are concentrated under reduced pressure, the residue ispartioned between 10% strength citric acid solution and ethyl acetateand the aqueous phase is extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulfate and concentrated. Theresidue is purified by preparative

HPLC. This gives 15 mg (5% of theory) of the title compound.

¹H NMR (200 MHz, DMSO-d₆): δ=13.33 (s, 1H, br), 9.70 (s, 1H), 8.20 (m,1H), 7.96 (s, 1H), 7.85 (d, 1H), 7.42 (dd, 1H) ppm.

HPLC: R_(t)=4.4 min (Method H)

MS (ESIpos): m/z=311 (M+NH₄)⁺

EXAMPLE 43A 7-Cyano-1-benzothiophene-2-carboxylic acid

1.6 g (7.36 mmol) of methyl 7-cyano-1-benzothiophene-2-carboxylate gives1.5 g of a mixture of starting material and product which is usedwithout further purification.

EXAMPLE 44A 6-Cyano-1-benzothiophene-2-carboxylic acid

0.6 g (2.76 mmol) of methyl 6-cyano-1-benzothiophene-2-carboxylate give0.49 g (61.6% of theory) of the desired product.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=222 (M+H)⁺

EXAMPLE 45A Thieno[2,3-f][1,3]benzodioxole-6-carboxylic acid

700 mg (2.3 mmol) of methyl thieno[2,3-f][1,3]benzodioxole-6-carboxylategive 513 mg (50% of theory) of a mixture of starting material andproduct which is used without further purification.

HPLC: R_(t)=3.9 min (Method H)

EXAMPLE 46A 6-Bromo-1-benzothiophene-2-carboxylic acid

4.0 g (14.8 mmol) of methyl 6-bromo-1-benzothiophene-2-carboxylate give3.55 g (93.5% of theory) of the desired product.

¹H NMR (400 MHz, DMSO-d₆): δ=13.48 (s, 1H, br), 8.38 (s, 1H), 8.22 (s,1H), 7.96 (d, 1H), 7.63 (m, 1H) ppm.

HPLC: R_(t)=4.5 min (Method H)

EXAMPLE 47A 5-Nitro-1-benzothiophene-2-carboxylic acid

1.10 g (4.39 mmol) of methyl 5-nitro-1-benzothiophene-2-carboxylate give0.93 g (94.8% of theory) of the desired product.

¹H NMR (400 MHz, DMSO-d₆): δ=13.88 (s, 1H, br), 8.98 (s, 1H), 8.38-8.25(m, 3H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=241 (M+NH₄)⁺

EXAMPLE 48A 7-Bromo-1-benzothiophene-2-carboxylic acid

10.0 g (36.9 mmol) of methyl 7-bromo-1-benzothiophene-2-carboxylate give8.99 g (91.0% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=13.76 (s, 1H, br), 8.28 (s, 1H), 8.07 (d,1H), 7.78 (d, 1H), 7.46 (dd, 1H) ppm.

HPLC: R_(t)=4.4 min (Method H)

EXAMPLE 49A 6-Nitro-1-benzothiophene-2-carboxylic acid

16 g (67.4 mmol) of methyl 6-nitro-1-benzothiophene-2-carboxylate give15.0 g (99.9% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=8.91 (d, 1H), 8.15 (dd, 1H), 8.02 (d, 1H),7.69 (s, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=241 (M+NH₄)⁺

EXAMPLE 50A 7-Trifluoromethyl-1-benzothiophene-2-carboxylic acid

4.2 g (16.2 mmol) of methyl7-trifluoromethyl-1-benzothiophene-2-carboxylate give 3.89 g (97.8% oftheory) of the desired product.

¹H NMR (500 MHz, DMSO-d₆): δ=13.88 (s, 1H, br), 8.35 (d, 1H), 8.28 (s,1H), 7.97 (d, 1H), 7.70 (dd, 1H) ppm.

HPLC: R_(t)=4.4 min (Method H)

MS (ESIpos): m/z=247 (M+H)⁺

EXAMPLE 51A 5-Trifluoromethyl-1-benzothiophene-2-carboxylic acid

4.28 g (18.5 mmol) of methyl5-trifluoromethyl-1-benzothiophene-2-carboxylate give 3.62 g (79.4% oftheory) of the desired product.

¹H NMR (400 MHz, DMSO-d₆): δ=13.78 (s, 1H, br), 8.47 (s, 1H), 8.32 (d,1H), 8.27 (s, 1H), 7.81 (d, 1H) ppm.

HPLC: R_(t)=4.5 min (Method H)

MS (ESIpos): m/z=246 (M⁺)

EXAMPLE 52A 7-Chloro-1-benzothiophene-2-carboxylic acid

500 mg (2.21 mmol) of methyl 7-chloro-1-benzothiophene-2-carboxylategive 391.6 mg (82.7% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d6): δ=13.78 (s, 1H, br), 8.20 (s, 1H), 8.03 (d,1H), 7.66 (d, 1H), 7.53 (dd, 1H) ppm.

HPLC: R_(t)=4.2 min (Method H)

MS (ESIpos): m/z=212 (M⁺)

EXAMPLE 53A 7-Fluoro-1-benzothiophene-2-carboxylic acid

3.27 g (15.6 mmol) of methyl 7-fluoro-1-benzothiophene-2-carboxylategive 3.05 g (100% of theory) of the desired product.

¹H NMR (200 MHz, CDCl₃): δ=8.05 (d, 1H), 7.68 (d, 1H), 7.38 (m, 1H),7.15 (m, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=214 (M+NH₄)⁺

EXAMPLE 54A 7-Methoxy-1-benzothiophene-2-carboxylic acid

300 mg (1.35 mmol) of methyl 7-methoxy-1-benzothiophene-2-carboxylategive 257.8 mg (85.3% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=13.52 (s, 1H, br), 8.10 (s, 1H), 7.59 (d,1H), 7.43 (dd, 1H), 7.08 (dd, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=226 (M+NH₄)⁺

EXAMPLE 55A 5-Fluoro-1-benzothiophene-2-carboxylic acid

1.0 g (4.76 mmol) of methyl 5-fluoro-1-benzothiophene-2-carboxylategives 865 mg (92.7% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=7.98 (dd, 1H), 7.77 (s, 1H), 7.72 (dd, 1H),7.29 (ddd, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=196 (M⁺)

EXAMPLE 56A 4-Fluoro-1-benzothiophene-2-carboxylic acid

3.0 g (14.3 mmol) of methyl 4-fluoro-1-benzothiophene-2-carboxylate give2.66 g (91.1% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d6): δ=13.78 (s, 1H, br), 8.05 (s, 1H), 7.92 (d,1H), 7.55 (ddd, 1H), 7.29 (dd, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=196 (M⁺)

EXAMPLE 57A 5,7-Difluoro-1-benzothiophene-2-carboxylic acid

2.4 g (10.5 mmol) of methyl 5,7-difluoro-1-benzothiophene-2-carboxylategive 2.1 g (93.1% of theory) of the desired product.

hu 1H NMR (200 MHz, DMSO-d₆): δ=13.88 (s, 1H, br), 8.17 (d, 1H), 7.77(dd, 1H), 7.56 (m, 1H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=214 (M⁺)

EXAMPLE 58A 5,6-Dimethoxy-1-benzothiophene-2-carboxylic acid

1.0 g (2.97 mmol) of methyl 5,6-dimethoxy-1-benzothiophene-2-carboxylategives 0.77 g (99% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=13.17 (s, 1H, br), 7.93 (s, 1H), 7.58 (s,1H), 7.48 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H) ppm.

HPLC: R_(t)=3.7 min (Method H)

MS (ESIpos): m/z=239 (M⁺), 256 (M+NH₄)⁺

EXAMPLE 59A 6-Methoxy-1-benzothiophene-2-carboxylic acid

2.52 g (11.34 mmol) of methyl 6-methoxy-1-benzothiophene-2-carboxylategive 2.26 g (95.7% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=13.29 (s, 1H, br), 8.01 (s, 1H), 7.88 (d,1H), 7.60 (d, 1H), 7.07 (dd, 1H), 3.86 (s, 3H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=209 (M+H⁺), 226 (M+NH₄)⁺

EXAMPLE 60A 4-Nitro-1-benzothiophene-2-carboxylic acid

1.0 g (4.22 mmol) of methyl 4-nitro-1-benzothiophene-2-carboxylate gives0.89 g (94.1% of theory) of the desired product.

¹H NMR (200 MHz, DMSO-d₆): δ=14.08 (m, 1H, br), 8.58 (d, 1H), 8.57 (s,1H), 8.42 (d, 1H), 7.77 (dd, 1H) ppm.

HPLC: R_(t)=4.0 min (Method H)

MS (ESIpos): m/z=241 (M+NH₄)⁺

EXAMPLE 61A 7-Nitro-1-benzothiophene-2-carboxylic acid

3.6 g (13.7 mmol) of methyl 7-nitro-1-benzothiophene-2-carboxylate give3.08 g (99.5% of theory) of the desired product.

¹H NMR (300 MHz, DMSO-d₆): δ=13.79 (s, 1H, br), 8.58 (d, 1H), 8.51 (d,1H), 8.33 (s, 1H), 7.78 (dd, 1H) ppm.

HPLC: R_(t)=4.0 min (Method H)

MS (ESIpos): m/z=241 (M+NH₄)⁺

EXAMPLE 62AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzothiophene-2-carboxamidehydrochloride

290 mg (1.30 mmol) of 6-nitro-1-benzothiophene-2-carboxylic acid, 258.7mg (1.30 mmol) of R-3-aminoquinuclidine dihydrochloride, 592.8 mg (1.56mmol) of HATU, 604.5 mg (4.68 mmol) of N,N-diisopropylethylamine and 2.0ml of DMF are reacted according to the general procedure. The reactionmixture is purified by preparative

HPLC. The product fractions are combined, 1N hydrochloric acid is addedand the mixture is then concentrated and dried under high vacuum. Thisgives 297 mg (62.1% of theory) of the title compound.

¹H NMR (400 MHz, methanol-d₄): δ=8.95 (s, 1H), 8.29 (dd, 1H), 8.20 (s,1H), 8.11 (d, 1H), 4.47 (m, 1H), 3.82 (m, 1H), 3.52-3.22 (m, 5H), 2.40(m, 1H), 2.28 (m, 1H), 2.11 (m,2H), 1.97(m, 1H) ppm.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=332 (M+H)⁺ (free base).

EXAMPLE 63AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-6-nitro-1-benzothiophene-2-carboxamide

427 mg (1.66 mmol) of 3-chloro-6-nitro-1-benzothiophene-2-carboxylicacid, 300 mg (1.51 mmol) of R-3-aminoquinuclidine dihydrochloride, 687.4mg (1.81 mmol) of HATU, 701 mg (5.43 mmol) of N,N-diisopropylethylamineand 4.0 ml of DMF are reacted according to the general procedure. 20 mlof methanol and 4 g of Dowex WX2-200 are added, and the mixture isstirred at RT for 1 h. The mixture is filtered and washed successivelywith water, methanol, methanol/trifluoroacetic acid 9:1 andmethanol/trifluoroacetic acid 1:1. Evaporation of the filtrate gives 270mg (49% of theory) of the title compound.

¹H NMR (200 MHz, DMSO-d₆): δ=9.24 (d, 1H), 8.77 (d, 1H), 8.38 (dd, 1H),8.11 (d, 1H), 3.97 (m, 1H), 3.70-3.22 (m, 2H), 3.14 (m, 1H), 2.97-2.44(m, 4H), 1.93 (m, 1H), 1.83 (m, 1H), 1.60 (m, 2H), 1.39 (m, 1H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=366 (M+H)⁺ (free base).

WORKING EXAMPLES EXAMPLE 1N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzothiophene-2-carboxamidehydrochloride

133.7 mg (0.52 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid,155.4 mg (0.78 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 296.7mg (0.78 mmol) of HATU, 369.8 mg (2.86 mmol) ofN,N-diisopropylethylamine and 1.5 ml of DMF are reacted according to thegeneral procedure (variant A). The reaction mixture is purified bypreparative HPLC. The product is dissolved in acetonitrile, and anexcess of 1N hydrochloric acid is added. The solvent is then removed.175 mg (84% of theory) of the title compound are isolated.

¹H NMR (200.1 MHz, DMSO-d₆): δ=9.44 (br. s, 1H), 8.95 (d, 1H), 8.30-8.10(m, 2H), 8.03 (d, 1H), 7.60 (m, 1H), 4.38-4.20 (m, 1H), 3.80-3.55 (m,1H), 3.42-3.05 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.62 (m, 3H) ppm.

LC-MS (Method A): R_(t)=2.63 min., MS (ESIpos): m/z=365 (M+H)⁺ (freebase).

EXAMPLE 2N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzothiophene-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas described in example 1 using S-3-aminoquinuclidine dihydrochloride.174 mg (83% of theory) of the title compound are isolated. Theanalytical data correspond to those of the enantiomeric compound fromexample 1.

EXAMPLE 3N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1-benzothiophene-2-carboxamidehydrochloride

102.1 mg (0.52 mmol) of 6-fluoro-1-benzothiophene-2-carboxylic acid,155.4 mg (0.78 mmol) of R-3-aminoquinuclidine dihydrochloride, 296.7 mg(0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamineand 1.5 ml of DMF are reacted according to the general procedure(variant A). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in acetonitrile, and an excess of 1N hydrochloricacid is added. The solvent is then removed. 22 mg (14% of theory) of thetitle compound are isolated.

LC-MS (Method B): R_(t)=1.22 min., MS (ESIpos): m/z=305 (M+H)⁺ (freebase).

EXAMPLE 4N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methyl-1-benzothiophene-2-carboxamidehydrochloride

100.0 mg (0.52 mmol) of 5-methyl-1-benzothiophene-2-carboxylic acid,155.4 mg (0.78 mmol) of R-3-aminoquinuclidine dihydrochloride, 296.7 mg(0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamineand 1.5 ml of DMF are reacted according to the general procedure(variant A). The reaction mixture is purified by preparative

HPLC. The product is dissolved in THF, and excess of 1N hydrochloricacid is added. The solvent is then removed. 57 mg (36% of theory) of thetitle compound are isolated.

MS (ESIpos): m/z=301 (M+H)⁺ (free base)

LC-MS (Method A): R_(t)=2.50 min., MS (ESIpos): m/z=301 (M+H)⁺ (freebase).

EXAMPLE 5N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methyl-1-benzothiophene-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas described in example 4 using S-3-aminoquinuclidine dihydrochloride.117 mg (75% of theory) of the title compound are isolated. Theanalytical data correspond to those of the enantiomeric compound fromexample 4.

EXAMPLE 6N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]thieno[3,2-b]pyridine-2-carboxamide

35 mg (0.20 mmol) of thieno[3,2-b]pyridine-2-carboxylic acid, 58.3 mg(0.29 mmol) of R-3-aminoquinuclidine dihydrochloride, 111.4 mg (0.29mmol) of HATU, 138.8 mg (1.07 mmol) of N,N-diisopropylethylamine and 1.5ml of DMF are reacted according to the general procedure (variant A).The reaction mixture is purified by preparative

HPLC and then subjected to fine purification on silica gel 60 (mobilephase:dichloromethane/methanol/ammonia 90:9:1). 44 mg (78% of theory) ofthe title compound are isolated.

¹H NMR (400.1 MHz, DMSO-d₆): δ=8.74 (d, 1H), 8.69 (d, 1H), 8.51 (d, 1H),8.41 (s, 1H), 7.45 (dd, 1H), 4.02-3.92 (m, 1H), 3.55-3.38 (m, 1H),2.95-2.85 (m, 1H), 2.78-2.63 (m, 4H), 1.95-1.80 (m, 2H), 1.68-1.52 (m,2H), 1.40-1.30 (m, 1H) ppm

MS (ESIpos): m/z=288 (M+H)⁺ (free base)

LC-MS (Method A): R_(t)=0.39 min., MS (ESIpos): m/z=288 (M+H)⁺ (freebase).

EXAMPLE 7N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]thieno[3,2-b]pyridine-2-carboxamide

The experiment is carried out in the same manner and on the same scaleas described in example 6 using S-3-aminoquinuclidine dihydrochloride.38 mg (68% of theory) of the title compound are isolated. The analyticaldata correspond to those of the enantiomeric compound from example 6.

EXAMPLE 8N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]thieno[2,3-b]pyridine-2-carboxamidehydrochloride

45.0 mg (0.25 mmol) of thieno[2,3-b]pyridine-2-carboxylic acid, 75.0 mg(0.38 mmol) of R-3-aminoquinuclidine dihydrochloride, 143.2 mg (0.38mmol) of HATU, 178.5 mg (1.38 mmol) of N,N-diisopropylethylamine and 1.5ml of DMF are reacted according to the general procedure (variant A).The reaction mixture is purified by preparative

HPLC. 37 mg (51% of theory) of the title compound are isolated.

¹H NMR (200.1 MHz, DMSO-d₆): δ=9.49 (br. s, 1H), 8.93 (d, 1H), 8.67 (dd,1H), 8.42 (dd, 1H), 8.19 (s, 1H), 7.52 (dd, 1H), 4.38-4.20 (m, 1H),3.80-3.55 (m, 1H), 3.42-3.05 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.62 (m,3H) ppm.

MS (ESIpos): m/z=288 (M+H)⁺ (free base)

LC-MS (Method A): R_(t)=0.37 min.,

MS (ESIpos): m/z=288 (M+H)⁺ (free base).

EXAMPLE 9rac-N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-nitro-1-benzothiophene-2-carboxamidehydrochloride

At RT, initially 244 mg (0.76 mmol) of TBTU and 104 mg (0.78 mmol) ofHOBt followed by 153 mg (0.77 mmol) of 3-aminoquinuclidinedihydrochloride are added to a solution of 180 mg (0.81 mmol) of5-nitrothiophene-2-carboxylic acid and diiso-propylethylamine (0.8 ml)in 4 ml of DMF. The mixture is stirred at RT for 4 h. For work-up, themixture is concentrated and the residue is taken up in a mixture ofchloroform and excess aqueous sodium hydroxide solution. The phases areseparated and the aqueous phase is repeatedly re-extracted withchloroform. The combined organic phases are dried over sodium sulfateand concentrated, and the crude product is chromatographed on silica gel(mobile phase: chloroform/methanol/conc. ammonia 100:5:0.5→100:20:2).The resulting product is taken up in THF, excess HCl in diethyl ether isadded, then the mixture is concentrated and the product is dried underhigh vacuum. 136 mg (47% of theory) of the hydrochloride are obtained.

hu 1H NMR (200.1 MHz, DMSO-d₆): δ=10.20 (br. s, 1H), 9.32 (d, 1H), 8.90(d, 1H), 8.55 (s, 1H), 8.40-8.20 (m, 2H), 4.40-4.35 (m, 1H), 3.75-3.60(m, 1H), 3.42-3.15 (m, 4H), 2.28-2.05 (m, 2H), 2.00-1.65 (m, 3H) ppm.

MS (ESIpos): m/z=332 (M+H)⁺ (free base).

EXAMPLE 10rac-N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-amino-1-benzothiophene-2-carboxamidedihydrochloride

129 mg (0.35 mmol) ofrac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-nitro-1-benzothiophene-2-carboxamidehydrochloride are dissolved in a mixture of 5 ml of acetic acid and 3 mlof water. 114.7 mg (1.75 mmol) of zinc are added, and the mixture isstirred at RT for 5 h. The reaction mixture is filtered throughkieselguhr, the solvent is removed and the residue is taken up indichloromethane. The resulting solution is washed with IN aqueous sodiumhydroxide solution. The organic phase is dried over sodium sulfate andthe solvent is then removed under reduced pressure. The resulting solidis dissolved in a little THF, and an excess of 1N HCl in diethyl etheris added. The THF is then distilled off. 103 mg (80% of theory) of thetitle compound are isolated.

LC-MS (Method A): R_(t)=0.36 min., MS (ESIpos): m/z=302 (M+H)⁺ (freebase).

EXAMPLE 11rac-N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-acetylamino-1-benzothiophene-2-carboxamidehydrochloride

41.0 mg (0.12 mmol) ofrac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-amino-1-benzothio-phene-2-carboxamidedihydrochloride and 36.8 mg (0.36 mmol) of triethylamine are dissolvedin 1.5 ml of DMF. At 0° C., 14.3 mg (0.18 mmol) of acetyl chloride areadded, and the mixture is stirred at RT overnight. The reaction mixtureis purified by preparative

HPLC. 29 mg (63% of theory) of the title compound are isolated.

¹H NMR (400.1 MHz, DMSO-d₆): δ=10.55 (br. s, 1H), 10.25 (s, 1H), 9.20(d, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.90 (d, 1H), 7.56 (m, 1H),4.38-4.25 (m, 1H), 3.65-3.55 (m, 1H), 3.50-3.35 (m, 2H), 3.25-3.10 (m,3H), 2.22-2.10 (m, 2H), 2.07 (s, 3H), 1.95-1.80 (m, 2H), 1.80-1.70 (m,1H) ppm.

LC-MS (Method A): R_(t)=1.22 min., MS (ESIpos): m/z=344 (M+H)⁺ (freebase).

EXAMPLE 12N-(1-Azabicyclo[2.2.2]oct-3-yl)thieno[2,3-b]quinoline-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 9, 242 mg(1.05 mmol) of thieno[2,3-b]quinoline-2-carboxylic acid [lit.: B. Bhatet al., Synthesis, 673ff. (1984)] gives a total of 314 mg (83% oftheory) of the title compound as a colorless solid.

¹H NMR (300.1 MHz, DMSO-d₆): δ=10.50 (br. s, 1H), 9.45 (d, 1H), 9.02 (s,1H), 8.58 (s, 1H), 8.22 (d, 1H), 8.10 (d, 1 H), 7.86 (m, 1H), 7.66 (m,1H), 3.72-3.58 (m, 2H), 3.50-3.40 (m, 2H), 3.30-3.15 (m, 3H), 2.28-2.15(m, 2H), 1.98-1.86 (m, 2H), 1.82-1.70 (m, 1H), 1.80-1.70 (m, 1H) ppm.

MS (ESIpos): m/z=338 (M+H)⁺ (free base).

EXAMPLE 13 N-(1-Azabicyclo[2.2.2]oct-3-yl)benzothiophene-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 9, 326 mg(1.83 mmol) of benzothiophene-2-carboxylic acid give a total of 332 mg(56% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, CD₃OD): δ=8.1 (s, 1H), 7.90 (m, 2H), 7.40 (m, 2H), 4.45(m, 1H), 3.80 (m, 1H), 3.55-3.20 (m, 5H), 2.4-2.20 (m, 2H), 2.10 (m,2H), 1.95 (m, 1H) ppm.

MS (ESIpos): m/z=287 (M+H)⁺ (free base).

EXAMPLE 14N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-chloro-1-benzothiophene-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 9, 122 mg(0.57 mmol) of 3-chlorobenzothiophene-2-carboxylic acid give a total of26 mg (13% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, CD₃OD): δ=8.00 (m, 2H), 7.60 (m, 2H), 4.55 (m, 1H),3.95 (m, 1H), 3.55-3.20 (m, 5H), 2.50 (m, 1H), 2.35 (m, 1H), 2.15 (m,2H), 2.05 (m, 1H) ppm.

MS (ESIpos): m/z=321 (M+H)⁺ (free base).

EXAMPLE 15N-(1-Azabicyclo[2.2.2]oct-3-yl)-7-bromo-1-benzothiophene-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 9, 271 mg(1.05 mmol) of 3-chlorobenzothiophene-2-carboxylic acid give a total of121 mg (29% of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, CD₃OD): δ=8.25 (s, 1H), 7.90 (d, 1H), 7.65 (d, 1H),7.40 (dd, 1H), 4.45 (m, 1H), 3.85 (m, 1H), 3.55-3.30 (m, 5H), 2.40 (m,1H), 2.35 (m, 1H), 2.10 (m, 2H), 2.00 (m, 1H) ppm.

MS (ESIpos): m/z=365 (M+H)⁺ (free base).

EXAMPLE 16 N-(1-Azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 9, 165 mg(0.91 mmol) of benzofuran-2-carboxylic acid give a total of 218 mg (78%of theory) of the title compound as a colorless solid.

¹H NMR (300 MHz, CDCl₃): δ=11.50 (s, 1H), 8.6 (d, 1H), 7.80 (s, 1H),7.60 (d, 1H), 7.55 (d, 1H), 7.35 (dd, 1H), 7.20 (dd, 1H), 4.65 (m, 1H),4.25 (m, 1H), 4.05 (m, 1H), 3.55 (m, 1H), 3.40-3.20 (m, 3H), 2.40 (m,1H), 2.25-2.00 (m, 2H), 1.95-1.75 (m, 2H) ppm.

MS (ESIpos): m/z=271 (M+H)⁺ (free base).

EXAMPLE 17 N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]benzofuran-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 16, thecorresponding reaction with 3R-aminoquinuclidine dihydrochloride givesthe corresponding enantiomerically pure product. The analytical datacorrespond to the those of example 16.

EXAMPLE 18N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-8-bromobenzothiophene-2-carboxamidehydrochloride

Analogously to the procedure for the compound from example 15, thecorresponding reaction with 3R-aminoquinuclidine dihydrochloride givesthe corresponding enantiomerically pure product. The analytical datacorrespond to those of example 15.

EXAMPLE 19N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1-benzofuran-2-carboxamidehydrochloride

190 mg (0.98 mmol) of 7-methoxybenzofuran-2-carboxylic acid, 200 mg(0.98 mmol) of R-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol)of HATU, 461 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml ofDMF are reacted according to the general procedure (variant B). Thereaction mixture is purified by preparative HPLC. An excess of 1Nhydrochloric acid is then added to the product. The solvent is removedunder reduced pressure. 202 mg (61% of theory) of the title compound areisolated.

¹H NMR (200 MHz, DMSO-d₆): δ=9.55 (s, 1H, br), 8.91 (d, 1H), 7.62 (s,1H), 7.36-7.22 (m, 2H), 7.11-7.07 (m, 1H), 4.43-4.29 (m, 1 H), 3.95 (s,3H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82(m, 2H), 1.80-1.60 (m, 1H) ppm.

MS (ESIpos): m/z=301 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.80 min., m/z=301 (M+H)⁺ (free base).

EXAMPLE 20N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas in example 19, but using S-3-aminoquinuclidine dihydrochloride. 180mg (54% of theory) of the title compound are isolated. The analyticaldata correspond to those of the enantiomeric compound from example 19.

EXAMPLE 21N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-dichloro-1-benzofuran-2-carboxamidehydrochloride

227 mg (0.98 mmol) of 5,7-dichlorobenzofuran-2-carboxylic acid, 200 mg(0.98mmol) of R-3-aminoquinuclidine dihydrochloride, 449 mg (1.18 mmol)of HATU, 458 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml ofDMF are reacted according to the general procedure (variant B). Thereaction mixture is purified by preparative HPLC. An excess of 1Nhydrochloric acid is then added to the product. The solvent is removedunder reduced pressure. 169 mg (46% of theory) of the title compound areisolated.

¹H NMR (200 MHz, DMSO-d₆): δ=10.01 (s, 1H, br), 9.11 (d, 1H), 7.94 (d,1H), 7.82 (s, 1H), 7.65 (d, 1H), 4.43-4.29 (m, 1 H), 3.70-3.55 (m, 1H),3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m,1H) ppm.

MS (ESIpos): m/z=339 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=3.21 min., m/z=339 (M+H)⁺ (free base).

EXAMPLE 22N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-dichloro-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 21, but using S-3-aminoquinuclidinedihydrochloride. 216 mg (58% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 21.

EXAMPLE 23N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamidehydrochloride

240 mg (0.98 mmol) of 5-bromobenzofuran-2-carboxylic acid, 200 mg (0.98mmol) of R-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) ofHATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMFare reacted according to the general procedure (variant B). The reactionmixture is purified by preparative HPLC. An excess of 1N hydrochloricacid is then added to the product. The solvent is removed under reducedpressure. 202 mg (53% of theory) of the title compound are isolated.

¹H NMR (200 MHz, DMSO-d₆): δ=9.38 (s, 1H, br), 8.88 (d, 1H), 7.60 (s,1H), 7.38-7.20 (m, 2H), 7.09 (dd, 1H), 4.43-4.29 (m, 1 H), 3.70-3.55 (m,1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60(m, 1H) ppm.

MS (ESIpos): m/z=349 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.71 min., m/z=349 (M+H)⁺ (free base).

EXAMPLE 24N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 23, but using S-3-aminoquinuclidinedihydrochloride. 277 mg (73% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 23.

EXAMPLE 25N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1-benzofuran-2-carboxamidehydrochloride

190 mg (0.98 mmol) of 5-chlorobenzofuran-2-carboxylic acid, 200 mg (0.98mmol) of R-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) ofHATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMFare reacted according to the general procedure (variant B). The reactionmixture is purified by preparative

HPLC. An excess of 1N hydrochloric acid is then added to the product.The solvent is removed under reduced pressure. 145 mg (43% of theory) ofthe title compound are isolated.

¹H NMR (200 MHz, DMSO-d₆): δ=9.78 (s, 1H, br), 9.07 (d, 1H), 7.91 (d,1H), 7.72 (d, 1H), 7.64 (s, 1H), 7.51 (dd, 1H), 4.43-4.29 (m, 1 H),3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m,2H), 1.80-1.60 (m, 1H) ppm.

MS (ESIpos): m/z=305 (M+H)⁺

LC-MS (Method D): R_(t)=2.96 min., m/z=305 (M+H)⁺ (free base).

EXAMPLE 26N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 25, but using S-3-aminoquinuclidinedihydrochloride. 100 mg (30% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 25.

EXAMPLE 27N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-5-nitro-1-benzofuran-2-carboxamidehydrochloride

230 mg (0.98 mmol) of 7-methoxy-5-nitro-1-benzofuran-2-carboxylic acid,200 mg (0.98 mmol) of R-3-aminoquinuclidine dihydrochloride, 450 mg(1.18 mmol) of HATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and2.0 ml of DMF are reacted according to the general procedure (variantB). The reaction mixture is purified by preparative HPLC. An excess of1N hydrochloric acid is then added to the product. The solvent isremoved under reduced pressure. 127 mg (34% of theory) of the titlecompound are isolated.

¹H NMR (200 MHz, DMSO-d₆): δ=9.56 (s, 1H, br), 9.10 (d, 1H), 8.42 (d,1H), 7.88 (d, 1H), 7.84 (s, 1H), 4.43-4.29 (m, 1 H), 4.10 (s, 3H),3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m,2H), 1.80-1.60 (m, 1H) ppm.

MS (ESIpos): m/z=346 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=3.16 min., m/z=346 (M+H)⁺ (free base).

EXAMPLE 28N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-5-nitro-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 27, but using S-3-aminoquinuclidinedihydrochloride. 83 mg (20% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 27.

EXAMPLE 295-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1-benzofuran-2-carboxamidedihydrochloride

Initially,N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-methoxy-5-nitro-1-benzofuran-2-carboxamidehydrochloride (120 mg, 0.31 mmol) is converted into the free base. Tothis end, the compound is taken up in ethyl acetate, and 30% strengthaqueous sodium hydroxide solution is added. The aqueous phase isextracted repeatedly with ethyl acetate. The extract is dried overmagnesium sulfate and the solvent is removed under reduced pressure. Thefree base is dissolved in 3 ml of methanol. 120 mg (1.84 mmol) ofammonium formate are added, and the mixture is heated under reflux for 4h. The reaction mixture is filtered through Celite, and the filter cakeis washed with ethanol and ethyl acetate. The crude product is subjectedto fine purification on silica gel 60 (mobile phase:dichloromethane→dichloromethane/methanol10:1→dichloromethane/methanol/ammonia 80:20:2). An excess of 4N HCl indioxane is added to the free base. The solvent is then removed underreduced pressure. 25 mg (17% of theory) of the title compound areisolated.

¹H NMR (400 MHz, D₂O): δ=7.62 (s, 1H), 7.40 (d, 1H), 7.07 (d, 1H),4.56-4.50 (m, 1H), 4.09 (s, 3H), 3.90-3.80 (m, 1H), 3.55-3.30 (m, 5H),2.50-2.40 (m, 1H), 2.35-2.21 (m, 1H), 2.20-2.05 (m, 2H), 2.06-1.93 (m,1H) ppm.

MS (ESIpos): m/z=316 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=0.43 min., m/z=316 (M+H)⁺ (free base).

EXAMPLE 30N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide

1248 mg (6.03 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 1000 mg(5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2291 mg (6.03mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15ml of DMF are reacted according to the general procedure (variant B).DMF is removed under reduced pressure. The reaction mixture is taken upin methanol and stirred together with acidic ion exchange resin (DowexWX2-200) for about 40 min. The loaded ion exchanger is washed six timeswith in each case 100 ml of methanol. It is then eluted usingmethanol/triethylamine 99:1 to 90:10. The solvent is removed underreduced pressure. The product is taken up in 1N aqueous sodium hydroxidesolution and extracted three times with ethyl acetate. The extract isdried on magnesium sulfate. 1100 mg (69% of theory) of the titlecompound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=8.67 (d, 1H), 8.36 (dd, 3H), 7.75 (d,1H), 7.67 (s, 1H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m,1H), 2.93-2.77 (m,4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75(m, 2H), 1.63-1.53 (m, 1H) ppm.

MS (ESIpos): m/z=316 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.28 min., m/z=316 (M+H)⁺ (free base).

EXAMPLE 31N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide

187 mg (0.90 mmol) of 5-nitrobenzofuran-2-carboxylic acid, 150 mg (0.75mmol) of (S)-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90 mmol)of HATU, 350.5 mg (3.71 mmol) of N,N-diisopropylethylamine and 5 ml ofDMF are reacted according to the general procedure (variant B). 169.1 mg(70% of theory) of the title compound are obtained. The analytical datacorrespond to those of the enantiomeric compound from example 30.

EXAMPLE 32N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzofuran-2-carboxamide

2.0 ml (4 mmol) of a 2 M tin(II) chloride solution in DMF are added toN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide(100 mg, 0.32 mmol). The mixture is stirred overnight. The reactionmixture is poured into water and made basic using 1N aqueous sodiumhydroxide solution. The aqueous phase is extracted six times with ethylacetate. The combined organic phases are dried over magnesium sulfate,and the solvent is removed under reduced pressure using a rotaryevaporator. The crude product is taken up in methanol and shakentogether with acidic ion exchange resin (Dowex WX2-200) for about 20min. The loaded ion exchanger is washed three times with in each ase 30ml of methanol, then with water/methanol 8:2, again with methanol, withdichloromethane and finally again with methanol. The product is elutedusing methanol/triethylamine 95:5. The solvent is removed under reducedpressure using a rotary evaporator. 52 mg (58% of theory) of the titlecompound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.35 (d, 1H), 7.32 (s, 1H), 6.97 (d,1H), 6.89 (dd, 3H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m,1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75(m, 2H), 1.63-1.53 (m, 1H) ppm.

MS (ESIpos): m/z=286 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.02 min., m/z=286 (M+H)⁺ (free base).

EXAMPLE 33N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzofuran-2-carboxamide

2.0 ml (4 mmol) of a 2 M tin(II) chloride solution in DMF are added toN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide(135 mg, 0.32 mmol), and the mixture is stirred at RT for 18 h. Thecrude product is taken up in methanol and shaken together with acidicion exchange resin (Dowex WX2-200) for about 20 min. The loaded ionexchanger is washed three times with in each case 30 ml of methanol,then with water/methanol 8:2, again with methanol, with dichloromethaneand finally again with methanol. The product is eluted usingmethanol/triethylamine 95:5. The solvent is removed under reducedpressure using a rotary evaporator, and 20 ml of 1N aqueous sodiumhydroxide solution are added to the crude mixture. The aqueous phase isextracted six times with in each case 20 ml of ethyl acetate. Thecombined organic phases are dried over magnesium sulfate and the solventis removed under reduced pressure using a rotary evaporator. 100.7 mg(82% of theory) of the title compound are isolated. The analytical datacorrespond to those of the enantiomeric compound from example 32.

EXAMPLE 34N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzofuran-2-carboxamide

1040 mg (5.02 mmol) of 6-nitrobenzofuran-2-carboxylic acid, 1000 mg(5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2290 mg (6.03mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 15ml of DMF are reacted according to the general procedure (variant B).DMF is removed under reduced pressure. The product is taken up in 100 mlof 1N aqueous sodium hydroxide solution and extracted three times within each case 50 ml of ethyl acetate. The combined organic phases aredried over magnesium sulfate and the solvent is removed under reducedpressure using a rotary evaporator. The reaction mixture is taken up inmethanol and, together with acidic ion exchange resin (Dowex WX2-200),stirred for about 40 min. The loaded ion exchange is washed six timeswith in each case 100 ml of methanol. The product is then eluted withmethanol/triethylamine 99:1 to 90:10. The solvent is removed underreduced pressure. The product is dried over magnesium sulfate. 1.75 g(99% of theory) of the title compound are isolated.

¹H NMR (200 MHz, CDCl₃): δ=8.45 (s, 1H), 8.25 (dd, 1H), 7.80 (d, 1H),7.56 (s, 1H), 7.05 (d, 1H), 4.35-4.18 (m, 1H), 3.1-2.82 (m, 5H),2.20-2.10 (m, 1H), 1.98-1.53 (m, 5H) ppm.

MS (ESIpos): m/z=316 (M+H)⁺ (free base)

HPLC: R_(t)=3.6 min (Method H)

LC-MS (Method D): R_(t=)2.62 min., m/z=316 (M+H)⁺ (free base).

EXAMPLE 35N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzofuran-2-carboxamide

15.0 ml (30 mmol) of a 2 M tin(II) chloride solution in DMF are added toN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzofuran-2-carboxamide(1550 mg, 4.92 mmol). The mixture is stirred overnight. The solvent isremoved under reduced pressure using a rotary evaporator. The crudeproduct is taken up in methanol and, together with acidic ion exchangeresin (Dowex WX2-200), shaken for about 1 h. The loaded ion exchanger iswashed with methanol, then with water, DMF, again with methanol, withdichloromethane and finally again with methanol. The product is elutedwith methanol/triethylamine 95:5. The solvent is removed under reducedpressure using a rotary evaporator. The crude product is purified onsilica gel 60 (mobile phase: dichloromethane/triethylamine100:1→dichloro-methane/methanol/triethylamine100:1:1→dichloromethane/methanol/triethylamine 90:10:1). 643 mg (46% oftheory) of the title compound are isolated.

MS (ESIpos): m/z=286 (M+H)⁺ (free base)

HPLC: R_(t)=2.6 min (Method H)

LC-MS (Method G): R_(t)=1.62 min., m/z=286 (M+H)⁺ (free base).

EXAMPLE 36N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-nitro-1-benzofuran-2-carboxamide

1040 mg (5.02 mmol) of 6-nitrobenzofuran-2-carboxylic acid, 1000 mg(5.02 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 2290 mg (6.03mmol) of HATU, 2250 mg (18.08 mmol) of N,N-diisopropylethylamine and 9ml of DMF are reacted according to the general procedure (variant B).DMF is removed under reduced pressure. The product is taken up in 100 mlof 1N aqueous sodium hydroxide solution and extracted three times within each case 50 ml of ethyl acetate. The combined organic phases arewashed eight times with 1N aqueous sodium hydroxide solution and oncewith saturated sodium chloride solution and then dried over magnesiumsulfate, and the solvent is removed under reduced pressure using arotary evaporator. 1.34 g (79% of theory) of the title compound areobtained.

¹H NMR (400 MHz, methanol-d₄): δ=8.35 (d, 1H), 8.18 (d, 1H), 7.71 (s,1H), 7.55 (dd, 1H), 4.25-4.18 (m, 1H), 3.40-3.31 (m, 1H), 3.10-2.97 (m,1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 2.03-1.92 (m, 1H), 1.84-1.75(m, 2H), 1.63-1.53 (m, 1H) ppm.

MS (ESIpos): m/z=316 (M+H)⁺ (free base)

HPLC: R_(t)=3.55 min (Method H)

LC-MS (Method E): R_(t)=3.15 min., m/z=316 (M+H)⁺ (free base).

EXAMPLE 37N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-amino-1-benzofuran-2-carboxamide

6.0 ml (12 mmol) of a 2 M tin(II) chloride solution in DMF are added toN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-nitro-1-benzofuran-2-carboxamide(1340 mg, 4.25 mmol). The mixture is stirred overnight. The solvent isremoved under reduced pressure using a rotary evaporator. The crudeproduct is taken up in methanol and, together with acidic ion exchangeresin (Dowex WX2-200), shaken for about 1 h. The loaded ion exchanger iswashed with methanol, then with water, again with methanol, with DMF,again with methanol, with THF, again with methanol, with dichloromethaneand finally once more with methanol. The product is eluted withmethanol/triethylamine 95:5. The solvent is removed under reducedpressure using a rotary evaporator. 1200 mg (98% of theory) of the titlecompound are obtained.

¹H NMR (300 MHz, DMSO-d₆): δ=8.18 (m, 1H), 7.40 (s, 1H), 6.98 (d, 1H),6.87 (d, 1H), 6.65 (d, 1H), 5.45 (br. s, 1H), 4.06-3.94 (m, 1H),3.29-3.15 (m, 1H), 3.04-2.88 (m, 1H), 2.85-2.65 (m, 4H), 1.98-1.77 (m,2H), 1.72-1.54 (m, 2H), 1.48-1.32 (m, 1H) ppm.

MS (ESIpos): m/z=286 (M+H)⁺ (free base)

HPLC: R_(t)=2.95 min (Method H)

LC-MS (Method E): R_(t)=3.03 min., m/z=286 (M+H)⁺ (free base).

EXAMPLE 38N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzofuran-2-carboxamide

55 mg (0.28 mmol) of 5,7-difluoro-1-benzofuran-2-carboxylic acid, 50 mg(0.25 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 114.6 mg (0.3mmol) of HATU, 117 mg (0.9 mmol) of N,N-diisopropylethylamine and 2.0 mlof DMF are reacted according to the general procedure (variant B). DMFis removed under reduced pressure and the crude product is dissolved in1N aqueous sodium hydroxide solution. The aqueous phase is extractedwith ethyl acetate. The combined organic phases are dried over magnesiumsulfate and the solvent is removed under reduced pressure using a rotaryevaporator. The crude product is taken up in methanol and, together withacidic ion exchange resin (Dowex WX2-200), shaken for about 20 min. Theloaded ion exchanger is washed three times with in each case 30 ml ofmethanol, then with water, again with methanol, with dichloromethane andfinally again with methanol. The product is eluted withmethanol/triethylamine 95:5. The solvent is removed under reducedpressure using a rotary evaporator. 40 mg (52% of theory) of the titlecompound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.58-7.55 (d, 1H), 7.34-7.29 (m, 1H),7.20-7.13 (m, 1H), 4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m,1H), 2.93-2.77 (m, 4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75(m, 2H), 1.63-1.53 (m, 1H) ppm.

MS (ESIpos): m/z=307 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.70 min., m/z=307 (M+H)⁺ (free base).

EXAMPLE 39N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzofuran-2-carboxamide

The experiment is carried out in the same manner and on the same scaleas for the compound from example 38, but using S-3-aminoquinuclidinedihydrochloride. 63 mg (82% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 38.

EXAMPLE 40N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide

143 mg (0.55 mmol) of 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid,100 mg (0.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 229.14 mg(0.6 mmol) of HATU, 234 mg (1.81 mmol) of N,N-diisopropylethylamine and2.0 ml of DMF are reacted according to the general procedure (variantB). DMF is removed under reduced pressure and the crude product isdissolved in 1N aqueous sodium hydroxide solution. The aqueous phase isextracted with ethyl acetate and washed with saturated sodium chloridesolution. The combined organic phases are dried over magnesium sulfateand the solvent is removed under reduced pressure using a rotaryevaporator. The crude product is taken up in methanol and, together withacidic ion exchange resin (Dowex WX2-200), shaken for about 20 min. Theloaded ion exchanger is washed three times with in each case 30 ml ofmethanol, then with water, again with methanol, with dichloromethane andfinally again with methanol. The product is eluted withmethanol/triethylamine 95:5. The solvent is removed under reducedpressure using a rotary evaporator. 181 mg (98% of theory) of the titlecompound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.59 (d, 1H), 7.53-7.46 (m, 2H),4.24-4.18 (m, 1H), 3.34-3.29 (m, 1H), 3.07-2.97 (m, 1H), 2.93-2.77 (m,4H), 2.13-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.75 (m, 2H), 1.63-1.53(m, 1H) ppm.

MS (ESIpos): m/z=367 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.92 min., m/z=367 (M+H)⁺ (free base).

EXAMPLE 41N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide

The experiment is carried out in the same manner and using half theamount of starting material and reagents as for the compound fromexample 40, using S-3-aminoquinuclidine dihydrochloride. 115 mg (47% oftheory) of the title compound are isolated. The analytical datacorrespond to those of the enantiomeric compound from example 40.

EXAMPLE 42N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzofuran-2-carboxamidehydrochloride

180 mg (1.00 mmol) of 5-fluoro-1-benzofuran-2-carboxylic acid, 200 mg(1.0 mmol) of R-3-aminoquinuclidine dihydrochloride, 460 mg (1.2 mmol)of HATU, 470 mg (3.62 mmol) of N,N-diisopropylethylamine and 2.0 ml ofDMF are reacted according to the general procedure (variant B). Thereaction mixture is purified by preparative HPLC. 1N aqueous sodiumhydroxide solution is added to the product purified in this manner, andthe mixture is extracted with ethyl acetate. The combined organic phasesare dried over sodium sulfate and the solvent is removed under reducedpressure. The product is dissolved in methanol and, using an excess of4N HCl in dioxane, converted into the hydrochloride. 256 mg (79% oftheory) of the title compound are isolated.

¹H NMR (200 MHz, DMSO-d₆): δ=10.23 (s, 1H, br), 9.12 (d, 1H), 7.76-7.59(m, 3H), 7.40-7.29 (m, 1H), 4.42-4.27 (m, 1H), 3.70-3.55 (m, 1H),3.45-3.10 (m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m,1H) ppm.

MS (ESIpos): m/z=289 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=1.4 min., m/z=289 (M+H)⁺ (free base).

EXAMPLE 43N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 42, but using S-3-aminoquinuclidinedihydrochloride. 224 mg (69% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 42.

EXAMPLE 44N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzofuran-2-carboxamidehydrochloride

130 mg (0.73 mmol) of 7-fluorobenzofuran-2-carboxylic acid, 150 mg (0.73mmol) of R-3-aminoquinuclidine dihydrochloride, 330 mg (0.87 mmol) ofHATU, 340 mg (2.62 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMFare reacted according to the general procedure (variant B). The reactionmixture is purified by preparative HPLC. An excess of 4 N HCl in dioxaneis then added to the product. The solvent is removed under reducedpressure. 116 mg (49% of theory) of the title compound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.67-7.53 (m, 1H), 7.40-7.22 (m, 2H),4.54-4.46 (m, 1H), 3.92-3.79 (m, 1H), 3.53-3.29 (m, 1H), 3.53-3.29 (m,4H), 2.46-2.39 (m, 1H), 2.31-2.20 (m, 1H), 2.17-2.07 (m, 2H), 2.06-1.92(m, 1H) ppm.

MS (ESIpos): m/z=289 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=2.50 min., m/z=289 (M+H)⁺ (free base).

EXAMPLE 45N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzofuran-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 44, but using S-3-aminoquinuclidinedihydrochloride. 115 mg (47% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 44.

EXAMPLE 46N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide

300 mg (1.25 mmol) of 7-bromobenzofuran-2-carboxylic acid, 248 mg (1.25mmol) of R-3-aminoquinuclidine dihydrochloride, 568 mg (1.494 mmol) ofHATU, 579 mg (4.48 mmol) of N,N-diisopropylethylamine and 5 ml of DMFare reacted according to the general procedure (variant B). The productis taken up in methanol and, together with acidic ion exchange resin(Dowex WX2-200), shaken for about 30 min. The loaded ion exchanger iswashed with DMF, water, methanol, dichloromethane, water, DMF and onceagain with methanol. The product is eluted with methanol/triethylamine90:10. The solvent is removed under reduced pressure using a rotaryevaporator. The pre-purified product is purified by preparative HPLC.320 mg (74% of theory) of the title compound are isolated.

¹H NMR (400 MHz, methanol-d₄): 8.41 (s, 1H), 7.70 (d, 1H), 7.68-7.60 (m,2H), 7.25 (t, 1H), 4.54-4.46 (m, 1H), 3.78-3.68 (m, 1H), 3.52-3.38 (m,1H), 3.38-3.22 (m, 4H), 2.46-2.38 (m, 1H), 2.30-2.18 (m, 1H), 2.18-2.04(m, 2H), 1.98-1.86 (m, 1H) ppm.

HPLC: R_(t)=3.80 min (Method H)

MS (ESIpos): m/z=349 (M+H)⁺ (free base)

LC-MS (Method G): R_(t)=2.67 min., m/z=349 (M+H)⁺ (free base).

EXAMPLE 47N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamidehydrochloride

3.8 g (15.77 mmol) of 6-bromobenzofuran-2-carboxylic acid, 3.14 g (15.77mmol) of R-3-aminoquinuclidine dihydrochloride, 7.19 g (18.92 mmol) ofHATU, 7.34 g (56.76 mmol) of N,N-diisopropylethylamine and 50 ml of DMFare reacted according to the general procedure (variant B). The crudeproduct is taken up in methanol and, together with acidic ion exchangeresin (Dowex WX2-200), shaken for about 20 min. The loaded ion exchangeris washed successively with methanol, dichloromethane and again withmethanol. The product is eluted with methanol/triethylamine 90:10. Thesolvent is removed under reduced pressure using a rotary evaporator.Finally, any last solvent residues are removed under high vacuum. 5.14 g(85% of theory) of the title compound are isolated. For analysis, asmall amount of product is converted into the hydrochloride using 4N HClin dioxane.

¹H NMR (200 MHz, DMSO-d₆): δ=10.55 (s, 1H, br), 9.22 (d, 1H), 8.05 (s,1H), 7.75-7.55 (m, 3H), 4.43-4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10(m, 5H), 2.25-2.00 (m, 2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m, 1H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=349 (M+H)⁺ (free base)

LC-MS (Method G): R_(t)=1.49 min., m/z=349 (M+H)⁺ (free base).

EXAMPLE 48N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]naphtho[1,2-b]furan-2-carboxamidehydrochloride

210 mg (0.98 mmol) of naphtho[1,2-b]furan-2-carboxylic acid, 200 mg(0.98 mmol) of R-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol)of HATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml ofDMF are reacted according to the general procedure (variant B). Thereaction mixture is purified by preparative HPLC. An excess of 1Naqueous hydrochloric acid is then added to the product. The solvent isremoved under reduced pressure. 74 mg (21% of theory) of the titlecompound are isolated.

¹H NMR (200 MHz, DMSO-d₆): δ=9.60 (s, 1H, br), 9.04 (d, 1H), 8.38 (d,1H), 8.31 (s, 1H), 8.13-8.00 (m, 2H), 7.84 (d, 1H), 7.74-7.56 (m, 2H),4.43-4.29 (m, 1H), 3.70-3.55 (m, 1H), 3.45-3.10 (m, 5H), 2.25-2.00 (m,2H), 1.98-1.82 (m, 2H), 1.80-1.60 (m, 1H) ppm.

MS (ESIpos): m/z=321 (M+H)⁺ (free base)

LC-MS (Method D): R_(t)=3.10 min., m/z=321 (M+H)⁺ (free base).

EXAMPLE 49N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]naphtho[1,2-b]furan-2-carboxamidehydrochloride

The experiment is carried out in the same manner and on the same scaleas for the compound from example 48, but using S-3-aminoquinuclidinedihydrochloride. 300 mg (85% of theory) of the title compound areisolated. The analytical data correspond to those of the enantiomericcompound from example 48.

EXAMPLE 50N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-cyclopropyl-2-oxoethyl)-1-benzofuran-carboxamide

150 mg (0.43 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide,27 mg (0.04 mmol) of rac-BINAP, 45 mg (0.47 mmol) of sodiumtert-butoxide and 20 mg (0.02 mmol) oftris(benzylideneacetone)dipalladium are dried under high vacuum for 1 h.Under an atmosphere of argon, 2 ml of dioxane are added. 72 mg (0.86mmol) of methyl cyclopropyl ketone are added dropwise, and the mixtureis heated at 85° C. overnight. The crude product is purified bypreparative HPLC. The solvent is removed under reduced pressure.Finally, any last solvent residues are removed under high vacuum. 75 mg(50% of theory) of the title compound are isolated.

¹H NMR (400 MHz, methanol-d₄): δ=7.62-7.49 (m, 3H), 7.35-7.30 (m, 1H),4.54-4.45 (m, 1H), 4.04 (s, 2H), 3.87-3.77 (m, 1H), 3.53-3.24 (m, 5H),2.42-2.31 (m, 1H), 2.30-2.19 (m, 1H), 2.20-2.04 (m, 3H), 1.98-1.88 (m,1H), 1.01-0.87 (m, 4H) ppm.

HPLC: R_(t)=3.7 min (Method H)

MS (ESIpos): m/z=353 (M+H)⁺.

EXAMPLE 51N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidehydrochloride

322.2 mg (1.81 mmol) of benzothiophene-2-carboxylic acid, 300.0 mg (1.51mmol) of R-3-aminoquinuclidine dihydrochloride, 687.4 mg (1.81 mmol) ofHATU, 701.1 mg (5.43 mmol) of N,N-diisopropylethylamine and 3.0 ml ofDMF are reacted according to the general procedure (variant B). Thereaction mixture is purified by preparative HPLC. The product isdissolved in a 1:1 mixture of methanol and 1N aqueous hydrochloric acidand then concentrated. 67 mg (13.8% of theory) of the title compound areobtained. The analytical data correspond to those of the racemate(example 13).

EXAMPLE 52N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamidehydrochloride

900.0 mg (3.50 mmol) of 4-bromo-1-benzothiophene-2-carboxylic acid,697.0 mg (3.50 mmol) of R-3-aminoquinuclidine dihydrochloride, 1597.1 mg(4.20 mmol) of HATU, 1628.7 mg (12.60 mmol) of N,N-diisopropylethylamineand 8.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in a 1:1 mixture of 4M HCl in dioxane and 1Naqueous hydrochloric acid and then concentrated. Recrystallization frommethanol/ethanol (1:10) gives 594 mg (42.1% of theory) of the titlecompound.

¹H NMR (300 MHz, DMSO-d₆): δ=9.81 (s, 1H, br), 8.76 (m, 1H), 8.33 (s,1H), 8.22 (s, 1H), 7.91 (d, 1H), 7.59 (dd, 1H), 4.15 (m, 1H), 3.51-2.93(m, 6H), 2.12-1.92 (m, 2H), 1.79 (m, 2H), 1.58 (m, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=366 (M, ⁸¹Br)⁺, 364 (M, ⁷⁹Br)⁺ (free base).

EXAMPLE 53N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]thieno[2,3-f][1,3]benzodioxole-6-carboxamidehydrochloride

122.8 mg (about 0.55 mmol) of a 1:1 mixture of methylthieno[2,3-f][1,3]benzo-dioxole-6-carboxylate andthieno[2,3-f][1,3]benzodioxole-6-carboxylic acid, 100 mg (0.50 mmol) ofR-3-aminoquinuclidine dihydrochloride, 229.1 mg (0.60 mmol) of HATU,233.7 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF arereacted according to the general procedure (variant B). The reactionmixture is purified by preparative HPLC. The product is dissolved in amixture of methanol and 4M HCl in dioxane and then concentrated anddried under high vacuum. 29 mg (15.8% of theory) of the title compoundare obtained.

¹H NMR (300 MHz, DMSO-d₆): δ=10.18 (s, 1H, br), 8.87 (d, 1H), 8.13 (s,1H), 7.56 (s, 1H), 7.42 (s, 1H), 6.12 (s, 2H), 4.29 (m, 1H), 3.90-3.55(m, 2H), 3.43-3.12 (m, 5H), 2.20 (m, 1H), 2.12 (m, 1H), 1.91 (m, 2H),1.75 (m, 1H) ppm.

HPLC: R_(t)=3.7 min (Method H)

MS (ESIpos): m/z=331 (M+H)⁺ (free base).

EXAMPLE 54N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]thieno[2,3-f][1,3]benzodioxole-6-carboxamidehydrochloride

122.8 mg (about 0.55 mmol) of a 1:1 mixture of methylthieno[2,3-f][1,3]benzo-dioxole-6-carboxylate andthieno[2,3-f][1,3]benzodioxole-6-carboxylic acid, 100 mg (0.50 mmol) ofS-3-aminoquinuclidine dihydrochloride, 229.1 mg (0.60 mmol) of HATU,233.7 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF arereacted according to the general procedure (variant B). The reactionmixture is purified by preparative HPLC. The product is dissolved in amixture of methanol and 4M HCl in dioxane and then concentrated anddried under high vacuum. 46 mg (25% of theory) of the title compound areobtained. The analytical data correspond to those of the enantiomericcompound from example 53.

EXAMPLE 55N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzothiophene-2-carboxamidehydrochloride

420 mg (1.88 mmol ) of 5-nitro-1-benzothiophene-2-carboxylic acid, 374.7mg (1.88 mmol) of R-3-aminoquinuclidine dihydrochloride, 858.6 mg (2.26mmol) of HATU, 875.5 mg (6.78 mmol) of N,N-diisopropylethylamine and 2.0ml of DMF are reacted according to the general procedure (variant B).The resulting precipitate is suspended in 1N HCl in diethyl ether,filtered off, washed twice with dichloromethane and dried under highvacuum. 523 mg (75.6% of theory) of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=10.45 (s, 1H, br), 9.43 (d, 1H), 8.37 (m,1H), 8.60 (s, 1H), 8.30 (m, 2H), 4.35 (m, 1H), 3.65 (m, 1H), 3.40 (m,2H), 3.23 (m, 3H) 2.24 (m, 1H), 2.17 (m, 1H), 1.93 (m, 2H), 1.76 (m, 1H)ppm.

MS (ESIpos): m/z=332 (M+H)⁺ (free base).

EXAMPLE 56N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-6-fluoro-1-benzothiophene-2-carboxamidehydrochloride

191.1 mg (0.83 mmol) of 3-chloro-6-fluoro-1-benzothiophene-2-carboxylicacid, 150.0 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride,343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) ofN,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to thegeneral procedure (variant B). The reaction mixture is purified bypreparative HPLC. The product is dissolved in 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 223.3 mg (77.4% of theory)of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=9.67 (m, 1H), 8.82 (d, 1H), 8.11 (dd, 1H),7.95 (dd, 1H), 7.50 (ddd, 1H), 4.33 (m, 1H), 3.80-3.08 (m, 6H), 2.27 (m,1H), 2.13 (m, 1H), 2.00-1.68 (m, 3H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=339 (M+H)⁺ (free base).

EXAMPLE 57N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-6-fluoro-1-benzothiophene-2-carboxamidehydrochloride

158 mg (0.69 mmol) of 3-chloro-6-fluoro-1-benzothiophene-2-carboxylicacid, 124 mg (0.62 mmol) of S-3-aminoquinuclidine dihydrochloride, 284.2mg (0.75 mmol) of HATU, 289.8 mg (2.24 mmol) ofN,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to thegeneral procedure (variant B). The reaction mixture is purified bypreparative HPLC. The product is dissolved in a mixture of 4M HCl indioxane and methanol and then reconcentrated. 190.5 mg (81.5% of theory)of the title compound are obtained. The analytical data correspond tothose of the enantiomeric compound from example 56.

EXAMPLE 58N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-fluoro-1-benzothiophene-2-carboxamidehydrochloride

162.6 mg (0.83 mmol) of 3-fluoro-1-benzothiophene-2-carboxylic acid,150.0 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride, 343.7 mg(0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamineand 2.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in 4M HCl in dioxane, then reconcentrated and driedunder high vacuum. 126.9 mg (48% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=9.84 (s, 1H, br), 9.11 (d, 1H), 8.39 (d,1H), 7.85 (d, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 4.32 (m, 1H), 3.78-3.14(m, 6H), 2.28-2.03 (m, 2H), 1.99-1.66 (m, 3H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=305 (M+H)⁺ (free base).

EXAMPLE 59N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-1-benzothiophene-2-carboxamidehydrochloride

162.6 mg (0.83 mmol) of 3-fluoro-1-benzothiophene-2-carboxylic acid,150.0 mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride, 343.7 mg(0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamineand 2.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative BPLC. Theproduct is dissolved in a mixture of methanol and 4M HCl in dioxane,then reconcentrated and dried under high vacuum. 162.8 mg (63% oftheory) of the title compound are obtained. The analytical datacorrespond to those of the enantiomeric compound from example 58.

EXAMPLE 60N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzothiophene-2-carboxamidehydrochloride

356.7 mg (1.68 mmol) of 3-chloro-1-benzothiophene-2-carboxylic acid, 334mg (1.68 mmol) of R-3-aminoquinuclidine dihydrochloride, 765.3 mg (2.01mmol) of HATU, 780.5 mg (6.04 mmol) of N,N-diisopropylethylamine and 2.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in 4M HCl in dioxane and then reconcentrated. 265 mg (44.2% oftheory) of the title compound are obtained. The analytical datacorrespond to those of the racemate (example 14).

EXAMPLE 61N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzothiophene-2-carboxamidehydrochloride

254.2 mg (1.20 mmol) of 3-chloro-1-benzothiophene-2-carboxylic acid, 238mg (1.20 mmol) of S-3-aminoquinuclidine dihydrochloride, 545.4 mg (1.43mmol) of HATU, 556.1 mg (4.30 mmol) of N,N-diisopropylethylamine and 2.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in 4M HCl in dioxane and then reconcentrated. 213 mg (49.9% oftheory) of the title compound are obtained. The analytical datacorrespond to those of the racemate (example 14).

EXAMPLE 62N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzothiophene-2-carboxamidedihydrochloride

385.0 mg (1.05 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzothio-phene-2-carboxamidehydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid andwater. 300.0 mg (4.59 mmol) of zinc are added, and the mixture is thenstirred at RT for 1 h. The reaction mixture is filtered throughkieselguhr, and the filter cake is washed with methanol. The filtrate isconcentrated under reduced pressure and the residue is purified bypreparative HPLC. The product fraction is dissolved in 4M HCl indioxane, concentrated under reduced pressure and recrystallized fromacetonitrile. 233 mg (59.5% of theory) of the title compound areobtained.

¹H NMR (400 MHz, D₂O): δ=7.99 (d, 1H), 7.96 (s, 1H), 7.88 (d, 1H), 7.38(dd, 1H), 4.36 (m, 1H), 3.76 (ddd, 1H), 3.43-3.19 (m, 5H), 2,32 (m, 1H),2.16 (m, 1H), 2.01 (m, 2H), 1.90 (m, 1H) ppm.

HPLC: R_(t)=2.9 min (Method H)

MS (ESIpos): m/z=302 (M+H)⁺ (free base).

EXAMPLE 63N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzothiophene-2-carboxamidedihydrochloride

422 mg (1.15 mmol) ofN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzo-thiophene-2-carboxamidehydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid andwater. 300.0 mg (4.59 mmol) of zinc are added, the mixture is thenstirred at RT for 1 h. The reaction mixture is filtered throughkieselguhr, and the filter cake is washed with methanol. The filtrate isconcentrated under reduced pressure and the residue is purified bypreparative HPLC. The product fraction is dissolved in 4M of HCl indioxane, concentrated under reduced pressure and recrystallized fromacetonitrile. 203 mg (47.3% of theory) of the title compound areobtained. The analytical data correspond to those of the enantiomericcompound from example 62.

EXAMPLE 64N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-trifluoromethyl-1-benzothiophene-2-carboxamidehydrochloride

204.0 mg (0.83 mmol) of 7-trifluoromethyl-1-benzothiophene-2-carboxylicacid, 150.0 mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride,343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) ofN,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to thegeneral procedure. The reaction mixture is purified by preparative HPLC.The product is dissolved in 4M HCl in dioxane, then reconcentrated underdried under high vacuum. 218.8 mg (74.3% of theory) of the titlecompound are obtained.

¹H NMR (400 MHz, DMSO-d₆): δ=10.50 (s, 1H, br), 9.41 (d, 1H), 8.60 (s,1H), 8.28 (d, 1H), 7.92 (d, 1H), 7.68 (dd, 1H), 4.36 (m, 1H), 3.64 (m,1H), 3.43 (m, 2H), 3.20 (m, 3H), 2.24 (m, 1H), 2.17 (m, 1H), 1.92 (m,2H), 1.74 (m, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=355 (M+H)⁺ (free base).

EXAMPLE 65N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-trifluoromethyl-1-benzothiophene-2-carboxamidehydrochloride

204.0 mg (0.83 mmol) of 7-trifluoromethyl-1-benzothiophene-2-carboxylicacid, 150.0 mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride,343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) ofN,N-diisopropylethylamine and 3.0 ml of DMF are reacted according to thegeneral procedure (variant B). The reaction mixture is purified bypreparative HPLC. The product is dissolved in 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 158.6 mg (53.9% of theory)of the title compound are obtained. The analytical data correspond tothose of the enantiomeric compound from example 64.

EXAMPLE 66N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-trifluoromethyl-1-benzothiophene-2-carboxamidehydrochloride

204.0 mg (0.83 mmol) of 5-trifluoromethyl-1-benzothiophene-2-carboxylicacid, 150.0 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride,343.7 mg (0.90 mmol) of HATU, 350.5 mg (2.71 mmol) ofN,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to thegeneral procedure (variant B). The reaction mixture is purified bypreparative HPLC. The product is dissolved in 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 89 mg (29% of theory) of thetitle compound are obtained.

¹H NMR (400 MHz, D₂O+DMSO-d₆): δ=8.36 (s, 1H), 8.19 (m, 2H), 7.80 (d,1H), 4.46 (m, 1H), 3.85 (m, 1H), 3.76-3.52 (m, 1H), 3.50-3.25 (m, 4H),2.40 (m, 1H), 2.22 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H) ppm.

HPLC: R_(t)=4.1 min (Method H)

MS (ESIpos): m/z=355 (M+H)⁺ (free base).

EXAMPLE 675-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzothiophene-2-carboxamidedihydrochloride

317 mg (0.83 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-5-nitro-1-benzothiophene-2-carboxamidehydrochloride are suspended in 2 ml of acetic acid. 300.0 mg (4.59 mmol)of zinc are added, and the mixture is then stirred at RT for 1 h. Thereaction mixture is filtered through kieselguhr, and the filter cake iswashed with methanol. The filtrate is concentrated under reducedpressure and the residue is purified by preparative HPLC. The productfraction is dissolved in 4M HCl in dioxane, concentrated under reducedpressure and recrystallized from acetonitrile. 154 mg (47.8% of theory)of the title compound are obtained.

¹H NMR (400 MHz, D₂O): δ=8.10 (d, 1H), 7.91 (d, 1H), 7.53 (dd, 1H), 4.52(m, 1H), 3.92 (m, 1H), 3.52-3.31 (m, 5H), 2.62 (s, 3H), 2,48 (m, 1H),2.25 (m, 1H), 2.17 (m, 2H), 2.05 (m, 1H) ppm.

MS (ESIpos): m/z=316 (M+H)⁺ (free base).

EXAMPLE 68N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-amino-1-benzothiophene-2-carboxamidedihydrochloride

87 mg (0.22 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzo-thiopene-2-carboxamidehydrochloride, 47.1 mg (0.26 mmol) of benzophenone-imine, 12.1 mg (0.02mmol) of rac-BINAP, 45.8 mg (0.48 mmol) of sodium tert-butoxide and 6.0mg (0.01 mmol) of Pd₂(dba)₃ are, under argon, added to a flask which hasbeen dried by heating. 1.5 ml of toluene are added, and the reactionmixture is heated at 80° C. After 30 min, 0.5 ml of THF is added,followed by a further 6.0 mg (0.01 mmol) of Pd₂(dba)₃ after 6 h. After afurther 6 h, the mixture is filtered (0.45 μm filter) and then purifiedby preparative HPLC. The resulting benzophenoneimine adduct is dissolvedin a 1:1 mixture of THF and methanol with addition of 20% by volume of1N hydrochloric acid. After 1 h at RT, the reaction mixture isconcentrated. The solid formed is triturated with acetonitrile andfiltered off. Drying under high vacuum gives 17 mg (21% of theory) ofthe title compound.

¹H NMR (400.1 MHz, D₂O): δ=8.11 (s, 1H), 7.89 (d, 1H), 7.53 (dd, 1H),7.37 (d, 1H), 4.48 (m, 1H), 3.87 (m, 1H), 3.52-3.30 (m, 5H), 2.44 (m,1H), 2.27 (m, 1H), 2.12 (m, 2H), 2.00 (m, 1H) ppm.

HPLC: R_(t)=2.9 min (Method H)

MS (ESIpos): m/z=302 (M+H)⁺ (free base).

EXAMPLE 69N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-chloro-1-benzothiophene-2-carboxamidehydrochloride

176.2 mg (0.83 mmol) of 7-chloro-1-benzothiophene-2-carboxylic acid, 150mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamine and 3.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of 4M HCl in dioxane and methanol and thenconcentrated. 175.2 mg (65.1% of theory) of the title compound areobtained.

¹H NMR (200 MHz, DMSO-d₆): δ=10.03 (s, 1H, br), 9.17 (d, 1H), 8.43 (s,1H), 7.98 (m, 1H), 7.63 (m, 1H), 7.52 (dd, 1H), 4.33 (m, 1H), 3.77-3.10(m, 6H), 2.28-2.02 (m, 2H), 1.92 (m, 2H), 1.75 (m, 1H) ppm.

HPLC: R_(t)=4.0 min (Method H)

MS (ESIpos): m/z=321 (M+H)⁺ (free base).

EXAMPLE 70 N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-chloro-1-benzothiophene-2-carboxamidehydrochloride

176.2 mg (0.83 mmol) of 7-chloro-1-benzothiophene-2-carboxylic acid, 150mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamine and 3.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of 4M HCl in dioxane and methanol and thenconcentrated. 231.9 mg (85.7% of theory) of the title compound areobtained. The analytical data correspond to those of the enantiomericcompound from example 69.

EXAMPLE 71N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-furoylamino)-1-benzothiophene-2-carboxamidehydrochloride

30 mg (0.08 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzo-thiophene-2-carboxamidedihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) oftriethylamine are added. At 0° C., 15.7 mg (0.12 mmol) offuran-2-carbonyl chloride are added. After 3 h of stirring at RT, thereaction mixture is separated by preparative HPLC. The product fractionis concentrated under reduced pressure and codistilled with 4M HCl indioxane. 12 mg (34.7% of theory) of the title compound are obtained.

¹H NMR (400 MHz, D₂O): δ=7.70 (d, 1H), 7.67 (m, 1H), 7.63 (m, 1H), 7.55(s, 1H), 7.28 (m, 1H), 7.14 (m, 1H), 6.60 (m, 1H), 4.24 (m, 1H), 3.70(m, 1H), 3.51-3.21 (m, 5H), 2.28 (m, 1H), 2.20 (m, 1H), 2.10 (m, 2H),2.00 (m, 1H) ppm.

HPLC: R_(t)=3.6 min (Method H)

LC-MS (Method F): m/z=396 (M+H)⁺ (free base), R_(t)=2.62 min.

EXAMPLE 72N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benzoylamino)-1-benzothiophene-2-carboxamidehydrochloride

30 mg (0.08 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzo-thiophene-2-carboxamidedihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) oftriethylamine are added. At 0° C., 16.9 mg (0.12 mmol) of benzoylchloride are added. After 3 h of stirring at RT, the reaction mixture isseparated by preparative HPLC. The product fraction is concentratedunder reduced pressure and codistilled with 4M HCl in dioxane. 9 mg(25.4% of theory) of the title compound are obtained.

LC-MS (Method F): m/z=406 (M+H)⁺ (free base), R_(t)=2.82 min.

EXAMPLE 736-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride

Method A):

15 mg (0.05 mmol) of6-[(tert-butoxycarbonyl)amino]-1-benzothiophene-2-carboxylic acid, 10.2mg (0.05 mmol) of R-3-aminoquinuclidine dihydrochloride, 21.4 mg (0.06mmol) of HATU, 21.8 mg (0.17 mmol) of N,N-diisopropylethylamine and 1 mlof DMF are reacted according to the general procedure (variant B). Thereaction mixture is purified by preparative HPLC. 5 ml of 4M HCl indioxane are added to the product, and the mixture is stirred at RT for30 min. The mixture is concentrated and the product is dried under highvacuum. 17 mg (98% of theory) of the title compound are obtained.

Method B):

247 mg (0.67 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzo-thiophene-2-carboxamidehydrochloride are suspended in 1.6 ml of 1N hydrochloric acid and 4.3 mlmethanol and, under argon, 25.6 mg of palladium on carbon (5%) areadded. Under an atmosphere of hydrogen (atmospheric pressure), themixture is stirred for 2 h. The contents of the flask are filteredthrough kieselguhr and the filtrate is evaporated to dryness underreduced pressure. 241 mg (95.6% of theory) of the title compound areobtained.

Method C):

Under argon, 730 mg (1.76 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamidehydrochloride, 638.9 mg (3.53 mmol) of benzophenoneimine, 109.8 mg (0.18mmol) of rac-BINAP, 508.2 mg (5.29 mmol) of sodium tert-butoxide and161.4 mg (0.18 mmol) of Pd₂(dba)₃ are added to a flask which had beendried by heating. 10 ml of a 1:1 mixture of THF and toluene are added,and the reaction mixture is heated at 85° C. overnight. The contents ofthe flask are concentrated to about 7 ml and purified by preparativeHPLC. The benzo-phenoneimine adduct formed is dissolved in 5 ml ofmethanol and 3 ml of 1N aqueous hydrochloric acid and stirred at RT for1 h. The solution is concentrated and the product is then recrystallizedfrom methanol/diethyl ether and purified further by preparative HPLC. 1Naqueous hydrochloric acid is added to the product fractions.Concentration and drying under high vacuum gives 67 mg (10.1% of theory)of the title compound.

¹H NMR (400 MHz, D₂O): δ=7.95 (m, 2H), 7.88 (m, 1H), 7.32 (m, 1H), 4.37(m, 1H), 3.80-3.69 (m, 2H), 3.40-3.18 (m, 4H), 2.32 (m, 1H), 2.16 (m,1H), 2.00 (m, 2H), 1.89 (m, 1H) ppm.

HPLC: R_(t)=2.7 min (Method H)

MS (ESIpos): m/z=302 (M+H)⁺ (free base).

EXAMPLE 74N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzothiophene-2-carboxamidehydrochloride

162.6 mg (0.83mmol) of 5-fluoro-1-benzothiophene-2-carboxylic acid,150.0 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride, 343.7 mg(0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamineand 3.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in a mixture of methanol and 4M HCl in dioxane,then reconcentrated and dried under high vacuum. 144.0 mg (56.1% oftheory) of the title compound are obtained.

¹H NMR (300 MHz, DMSO-d₆): δ=10.01 (s, 1H, br), 9.03 (d, 1H), 8.27 (s,1H), 8.08 (dd, 1H), 7.81 (dd, 1H), 7.38 (ddd, 1H), 4.32 (m, 1H), 3.67(m, 1H), 3.43-3.15 (m, 5H), 2.24 (m, 1H), 2.13 (m, 1H), 1.93 (m, 2H),1.77 (m, 1H) ppm.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=305 (M+H)⁺ (free base).

EXAMPLE 75N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-benzothiophene-2-carboxamidehydrochloride

162.6 mg (0.83 mmol) of 5-fluoro-1-benzothiophene-2-carboxylic acid, 150mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride, 343.7 mg (0.90mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamine and 3.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of 4M HCl in dioxane and methanol and thenreconcentrated. 127.6 mg (49.7% of theory) of the title compound areobtained. The analytical data correspond to those of the enantiomericcompound from example 74.

EXAMPLE 76N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1-benzothiophene-2-carboxamidehydrochloride

115 mg (0.55 mmol) of 7-methoxy-1-benzothiophene-2-carboxylic acid, 100mg (0.50 mmol) of R-3-aminoquinuclidine dihydrochloride, 229.1 mg (0.60mmol) of HATU, 233.7 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 176.9 mg (95.6% of theory)of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=9.45 (m, 1H), 8.86 (d, 1H), 8.20 (s, 1H),7.77 (d, 1H), 7.43 (dd, 1H), 7.06 (d, 1H), 4.31 (m, 1H), 3.98 (s, 3H),3.80-3.10 (m, 6H), 2.21 (m, 1H), 2.13 (m, 1H), 1.93 (m, 2H), 1.78 (m,1H) ppm.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=317 (M+H)⁺ (free base).

EXAMPLE 77N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1-benzothiophene-2-carboxamidehydrochloride

103.5 mg (0.50 mmol) of 7-methoxy-1-benzothiophene-2-carboxylic acid, 90mg (0.45 mmol) of S-3-aminoquinuclidine dihydrochloride, 206.2 mg (0.54mmol) of HATU, 210.3 mg (1.62 mmol) of N,N-diisopropylethylamine and 2.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 105.6 mg (66.2% of theory)of the title compound are obtained. The analytical data correspond tothose of the enantiomeric compound from example 76.

EXAMPLE 78N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-1-benzothiophene-2-carboxamidehydrochloride

197.1 mg (1.00 mmol) of 4-fluoro-1-benzothiophene-2-carboxylic acid,125.0 mg (0.63 mmol) of R-3-aminoquinuclidine dihydrochloride, 286.4 mg(0.75 mmol) of HATU, 292.1 mg (2.26 mmol) of N,N-diisopropylethylamineand 3.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in a mixture of methanol and 4M HCl in dioxane,then reconcentrated and dried under high vacuum. 160.1 mg (73.3% oftheory) of the title compound are obtained.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=305 (M+H)⁺ (free base).

EXAMPLE 79N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-1-benzothiophene-2-carboxamidehydrochloride

197.1 mg (1.00 mmol) of 4-fluoro-1-benzothiophene-2-carboxylic acid,125.0 mg (0.63 mmol) of S-3-aminoquinuclidine dihydrochloride, 286.4 mg(0.75 mmol) of HATU, 292.1 mg (2.26 mmol) of N,N-diisopropylethylamineand 3.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in a mixture of methanol and 4M HCl in dioxane,then reconcentrated and dried under high vacuum. 85.7 mg (40.1% oftheory) of the title compound are obtained. The analytical datacorrespond to those of the enantiomeric compound from example 78.

EXAMPLE 80N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzothiophene-2-carboxamidehydrochloride

177.5 mg (0.83 mmol) of 5,7-difluoro-1-benzothiophene-2-carboxylic acid,150.0 mg (0.75 mmol) of R-3-aminoquinuclidine dihydrochloride, 343.7 mg(0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamineand 3.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in a mixture of methanol and 4M HCl in dioxane,then reconcentrated and dried under high vacuum. 110.4 mg (40.8% oftheory) of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=10.14 (s, 1H, br), 9.26 (d, 1H), 8.40 (d,1H), 7.78 (dd, 1H), 7.52 (ddd, 1H), 4.31 (m, 1H), 3.65 (m, 1H),3.50-3.07 (m, 5H), 2.22 (m, 1H), 2.14 (m, 1H), 1.90 (m, 2H), 1.75 (m,1H) ppm.

HPLC: R_(t)=3.9 min (Method H)

MS (ESIpos): m/z=323 (M+H)⁺ (free base).

EXAMPLE 81N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5,7-difluoro-1-benzothiophene-2-carboxamidehydrochloride

177.5 mg (0.83 mmol) of 5,7-difluoro-1-benzothiophene-2-carboxylic acid,150.0 mg (0.75 mmol) of S-3-aminoquinuclidine dihydrochloride, 343.7 mg(0.90 mmol) of HATU, 350.5 mg (2.71 mmol) of N,N-diisopropylethylamineand 3.0 ml of DMF are reacted according to the general procedure(variant B). The reaction mixture is purified by preparative HPLC. Theproduct is dissolved in a mixture of methanol and 4M HCl in dioxane,then reconcentrated and dried under high vacuum. 109.3 mg (40.4% oftheory) of the title compound are obtained. The analytical datacorrespond to those of the enantiomeric compound from example 80.

EXAMPLE 82N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1-benzothiophene-2-carboxamidehydrochloride

100 mg (0.48 mmol) of 6-methoxy-1-benzothiophene-2-carboxylic acid, 86.9mg (0.44mmol) of R-3-aminoquinuclidine dihydrochloride, 199.2 mg (0.52mmol) of HATU, 203.13 mg (1.57 mmol) of N,N-diisopropylethylamine and1.5 ml of DMF are reacted according to the general procedure (variantB). The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 118.2 mg (76.7% of theory)of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=9.77 (s, 1H, br), 8.83 (d, 1H), 8.17 (s,1H), 7.85 (d, 1H), 7.60 (d, 1H), 7.07 (dd, 1H), 4.30 (m, 1H), 3.84 (s,3H), 3.79-3.45 (m, 2H), 3.39-3.10 (m, 4H), 2.20 (m, 1H), 2.10 (m, 1H),1.90 (m, 2H), 1.75 (m, 1H) ppm.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=317 (M+H)⁺ (free base).

EXAMPLE 83N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1-benzothiophene-2-carboxamidehydrochloride

100 mg (0.48 mmol) of 6-methoxy-1-benzothiophene-2-carboxylic acid, 86.9mg (0.44 mmol) of S-3-aminoquinuclidine dihydrochloride, 199.2 mg (0.52mmol) of HATU, 203.13 mg (1.57 mmol) of N,N-diisopropylethylamine and1.5 ml of DMF are reacted according to the general procedure (variantB). The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 112.5 mg (73% of theory) ofthe title compound are obtained. The analytical data correspond to thoseof the enantiomeric compound from example 82.

EXAMPLE 84N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzothiophene-2-carboxamidehydrochloride

320.8 mg (1.1 mmol) of 6-cyano-1-benzothiophene-2-carboxylic acid, 200mg (1.0 mmol) of R-3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21mmol) of HATU, 467.3 mg (3.62 mmol) of N,N-diisopropylethylamine and 4.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 222.1 mg (63.6% of theory)of the title compound are obtained.

¹H NMR (300 MHz, DMSO-d₆): δ=9.80 (m, 1H), 9.12 (d, 1H), 8.68 (s, 1H),8.37 (s, 1H), 8.16 (d, 1H), 7.83 (dd, 1H), 4.33 (m, 1H), 3.76-3.05 (m,6H), 2.23 (m, 1H), 2.13 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H) ppm.

HPLC: R_(t)=3.6 min (Method H)

MS (ESIpos): m/z=312 (M+H)⁺ (free base).

EXAMPLE 85N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzothiophene-2-carboxamidehydrochloride

112.2 mg (0.39 mmol) of 6-cyano-1-benzothiophene-2-carboxylic acid, 70mg (0.35 mmol) of S-3-aminoquinuclidine dihydrochloride, 160.4 mg (0.42mmol) of HATU, 163.5 mg (1.26 mmol) of N,N-diisopropylethylamine and 1.5ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 250.1 mg (41 % of theory) ofthe title compound are obtained. The analytical data correspond to thoseof the enantiomeric compound from example, 84.

EXAMPLE 86N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-nitro-1-benzothiophene-2-carboxamidehydrochloride

246.6 mg (1.10 mmol) of 4-nitro-1-benzothiophene-2-carboxylic acid, 200mg (1.00 mmol) of R-3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21mmol) of HATU, 467.4 mg (3.62 mmol) of N,N-diisopropylethylamine and 4.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 134.3 mg (35.6% of theory)of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=9.70 (s, 1H, br), 9.23 (d, 1H), 8.49 (s,1H), 8.57 (d, 1H), 8.43 (dd, 1H), 7.73 (dd, 1H), 4.32 (m, 1H), 3.82-3.10(m, 6H), 2.27 (m, 1H), 2.13 (m, 1H), 1.93 (m, 2H), 1.77 (m, 1H) ppm.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=332 (M+H)⁺ (free base).

EXAMPLE 87N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-nitro-1-benzothiophene-2-carboxamidehydrochloride

246.6 mg (1.10 mmol) of 4-nitro-1-benzothiophene-2-carboxylic acid, 200mg (1.00mmol) of S-3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21mmol) of HATU, 467.4 mg (3.62 mmol) of N,N-diisopropylethylamine and 4.0ml of DMF are reacted according to the general procedure (variant B).The reaction mixture is purified by preparative HPLC. The product isdissolved in a mixture of methanol and 4M HCl in dioxane, thenreconcentrated and dried under high vacuum. 128.5 mg (34.8% of theory)of the title compound are obtained after recrystallization frommethanol. The analytical data correspond to those of the enantiomericcompound from example 86.

EXAMPLE 886-(Acetylamino)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidehydrochloride

50 mg (0.12 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzo-thiophene-2-carboxamidedihydrochloride are initially charged in 0.3 ml of DMF, and 18.7 mg(0.18mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chlorideare added. After 16 h of stirring at RT, a further 18.7 mg (0.18 mmol)of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added.After a further 12 h of stirring at RT, the supernatant solution of thereaction mixture is purified by preparative HPLC. The product fractionsare concentrated and the residue is dissolved in a mixture of methanoland 4M HCl in dioxane, then reconcentrated and dried under high vacuum.8 mg (17.1 % of theory) of the title compound are obtained.

¹H NMR (400 MHz, methanol-d₄): δ=8.34 (m, 1H), 8.06 (s, 1H), 7.83 (d,1H), 7.47 (dd, 1H), 4.45 (m, 1H), 3.83 (m, 1H), 3.49 (m, 1H), 3.42-3.26(m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.17 (s, 3H), 2.10 (m, 2H), 1.95(m, 1H) ppm.

HPLC: R_(t)=3.3 min (Method H)

MS (ESIpos): m/z=344 (M+H)⁺ (free base).

EXAMPLE 89N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-amino-1-benzothiophene-2-carboxamidedihydrochloride

2 ml of methanol and 460 μl of 1N hydrochloric acid are added to 70 mg(0.19 mmol) of 4-nitro-1-benzothiophene-2-carboxylic acid. 7 mg ofpalladium-on-carbon (10%) are added, and the reaction mixture is thenhydrogenated at RT and atmospheric pressure for 2 h. The reactionmixture is filtered through kieselguhr and purified by preparative HPLC.The product fractions are concentrated, a mixture of methanol and 4M HClin dioxane is added and the mixture is then again concentrated and driedunder high vacuum. 75.5 mg (98.7% of theory) of the title compound areobtained.

HPLC: R_(t)=2.9 min (Method H)

MS (ESIpos): m/z=302 (M+H)⁺ (free base).

EXAMPLE 90N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-6-amino-1-benzothiophene-2-carboxamidedihydrochloride

83 mg (0.23 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-6-nitro-1-benzothiophene-2-carboxamidehydrochloride are dissolved in 1.5 ml of 2M tin(II) chloride solution inDMF and stirred at RT for 14 h. The reaction mixture is purified bypreparative HPLC. The product fractions are concentrated, dissolved in amixture of methanol and 4M HCl in dioxane, then again concentrated anddried under high vacuum. 53 mg (57.2% of theory) of the title compoundare obtained.

¹H NMR (300 MHz, methanol-d₄): δ=7.69 (d, 1H), 7.20 (d, 1H), 7.02 (dd,1H), 4.46 (m, 1H), 3.83 (m, 1H), 3.52-3.25 (m, 5H), 2.42 (m, 1H), 2.27(m, 1H), 2.11 (m, 2H), 2.02 (m, 1H) ppm.

HPLC: R_(t)=3.0 min (Method H)

MS (ESIpos): m/z=336 (M+H)⁺ (free base).

EXAMPLE 91N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(isopropylamino)-1-benzothiophene-2-carboxamidedihydrochloride

A solution of 150 mg (0.40 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride and 48 μl (0.65 mmol) of acetone in 1.5 ml of1,2-dichloroethane is adjusted to pH 4 using acetic acid. 254.8 mg (1.20mmol) of sodium triacetoxyborohydride are added, and the mixture isstirred at RT for 6 h. The contents of the flask are concentrated underreduced pressure and purified by preparative HPLC. The product fractionsare concentrated and the residue is dissolved in a 5:1 mixture ofacetonitrile and 1N hydrochloric acid, then again concentrated and driedunder high vacuum. 49 mg (29.4% of theory) of the title compound areobtained.

¹H NMR (300 MHz, methanol-d₄): δ=8.32 (s, 1H), 8.15 (m, 2H), 7.53 (dd,1H), 4.49 (m, 1H), 3.88 (m, 1H), 3.83 (m, 1H), 3.56 (m, 1H), 3.50-3.23(m, 4H), 2.39 (m, 1H), 2.31 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H), 1.39(d, 6H) ppm.

HPLC: R_(t)=3.1 min (Method H)

MS (ESIpos): m/z=344 (M+H)⁺ (free base).

EXAMPLE 926-[(Z)-Amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzo-thiophene-2-carboxamidedihydrochloride

800 mg (2.0 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzo-thiopene-2-carboxamidehydrochloride, 278.1 mg (4.0mmol) of hydroxylamine hydrochloride and829.5 mg (6.0 mmol) of potassium carbonate in 8 ml of an 8:1 mixture ofwater and ethanol are heated at 80° C. for 3 h. The mixture is purifiedby column chromatography on silica gel (mobile phase:dichloromethane/methanol/25% ammonia 100:20:4). The product fractionsare combined and concentrated, methanol and 4M HCl in dioxane are addedand the mixture is then again concentrated and dried under high vacuum.447.3 mg (53.6% of theory) of the title compound are obtained.

¹H NMR (200 MHz, DMSO-d₆): δ=11.15 (m, 1H), 10.22 (m, 1H), 9.36 (d, 1H),8.52 (s, 1H), 8.46 (m, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 4.33 (m, 1H),3.93-3.10 (m, 6H), 2.32-2.05 (m, 2H), 1.93 (m, 2H), 1.75 (m, 1H) ppm.

HPLC: R_(t)=2.9 min (Method H)

MS (ESIpos): m/z=345 (M+H)⁺ (free base).

EXAMPLE 93N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzothiophene-2-carboxamidehydrochloride

1.5 g (7.38 mmol) of 7-cyano-1-benzothiophene-2-carboxylic acid and 1.47g (7.38 mmol) of R-3-aminoquinuclidine dihydrochloride are initiallycharged in 25 ml of DMF. At 0° C., 1.70 g (8.86 mmol) of EDC, 1.20 g(8.86 mmol) of HOBt and 3.70 ml (26.6 mmol) of triethylamine are addedto the solution. The mixture is stirred at RT for 18 h. The reaction isterminated by addition of a 10% strength aqueous sodium bicarbonatesolution, and ethyl acetate is added. The resulting precipitate isfiltered off with suction. The mother liquor is extracted twice withethyl acetate. The organic phases are combined and concentrated. Thecrude product is purified by silica gel column chromatography (mobilephase: dichloromethane/methanol/25% ammonia 100:20:4). The productfractions are concentrated, dissolved in a mixture of methanol and 1Nhydrochloric acid, then again concentrated and dried under high vacuum.655.1 mg (24.5% of theory) of the title compound are obtained.

HPLC: R_(t)=3.7 min (Method H)

MS (ESIpos): m/z=312 (M+H)⁺ (free base).

EXAMPLE 94N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-nitro-1-benzothiophene-2-carboxamidehydrochloride

2.0 g (8.96 mmol) of 7-nitro-1-benzothiophene-2-carboxylic acid and 1.78g (8.96 mmol) of R-3-aminoquinuclidine dihydrochloride are initiallycharged in 25 ml of DMF. At 0° C., 2.06 g (10.75 mmol) of EDC, 1.45 g(10.75 mmol) of HOBt and 4.50 ml (32.26 mmol) of triethylamine are addedto the solution. The mixture is stirred at RT for 18 h. The reaction isterminated by addition of a 10% strength aqueous sodium bicarbonatesolution, and ethyl acetate is added. The resulting precipitate isfiltered off with suction. The mother liquor is extracted twice withethyl acetate. The organic phases are combined and concentrated. Boththe precipitate and the concentrated mother liquor are purified bysilica gel column chromatography (mobile phase:dichloromethane/methanol/25% ammonia 100:10:2). The product fractionsare concentrated, dissolved in a mixture of methanol and 1N hydrochloricacid, then again concentrated and dried under high vacuum. The resultingsolid is triturated with acetonitrile, filtered off with suction anddried at 50° C. under reduced pressure. 1.10 g (32.8% of theory) of thetitle compound are obtained.

¹H NMR (500 MHz, DMSO-d₆): δ=9.90 (s, 1H, br), 9.25 (d, 1H), 8.56 (d,1H), 8.50 (s, 1H), 8.49 (d, 1H), 7.78 (dd, 1H), 4.37 (m, 1H), 3.69 (m,1H), 3.62-3.19 (m, 5H), 2.23 (m, 1H), 2.14 (m, 1H), 1.93 (m, 2H), 1.78(m, 1H) ppm.

HPLC: R_(t)=3.8 min (Method H)

MS (ESIpos): m/z=332 (M+H)⁺ (free base).

EXAMPLE 95N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1-benzothiophene-2-carboxamidehydrochloride

40mg (0.11 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzo-thiophene-2-carboxamidehydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) ofN,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and16.61 (0.21 mmol) of methanesulfonyl chloride are added and the mixtureis stirred at room temperature for 16 h. The reaction mixture ispurified by preparative HPLC. The product is dissolved in a mixture of1N aqueous hydrochloric acid and acetonitrile, then reconcentrated anddried under high vacuum. 15 mg (33.8% of theory) of the title compoundare obtained.

¹H NMR (400 MHz, methanol-d₄): δ=8.07 (s, 1H), 7.87 (d, 1H), 7.81 (d,1H), 7.32 (dd, 1H), 4.44 (m, 1H), 3.83 (m, 1H), 3.48 (m, 1H), 3.42-3.24(m, 4H), 3.00 (s, 3H), 2.37 (m, 1H), 2.27 (m, 1H), 2.10 (m, 2H), 1.95(m, 1H) ppm.

HPLC: R_(t)=3.3 min (Method H)

MS (ESIpos): m/z=380 (M+H)⁺ (free base).

EXAMPLE 96N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[bis(phenylsulfonyl)amino]-1-benzo-thiophene-2-carboxamidehydrochloride

40 mg (0.11 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzo-thiophene-2-carboxamidehydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) ofN,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and27.2 μl (0.21 mmol) of benzenesulfonyl chloride are added and themixture is stirred at room temperature for 16 h. The reaction mixture ispurified by preparative HPLC. The product is dissolved in a mixture of1N aqueous hydrochloric acid and acetonitrile, then again concentratedand dried under high vacuum. 33 mg (50% of theory) of the title compoundare obtained.

¹H NMR (400 MHz, methanol-d₄): δ=8.13 (s, 1H), 7.94-7.82 (m, 5H), 7.78(m, 2H), 7.68-7.55 (m, 5H), 7.01 (dd, 1H), 4.45 (m, 1H), 3.84 (m, 1H),3.47 (m, 1H), 3.42-3.22 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m,2H), 1.95 (m, 1H) ppm.

HPLC: R_(t)=4.4 min (Method H)

MS (ESIpos): m/z=582 (M+H)⁺ (free base).

EXAMPLE 97N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(benzoylamino)-1-benzothiophene-2-carboxamidehydrochloride

40 mg (0.11 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzo-thiophene-2-carboxamidedihydrochloride are dissolved in 2 ml of DMF, and 59.6 μl (0.43 mmol) oftriethylamine are added. 30 mg (0.21 mmol) of benzoyl chloride areadded. The reaction mixture is stirred at RT for 18 h and then separatedby preparative HPLC. The product fraction is concentrated under reducedpressure, a mixture of acetonitrile and 1N hydrochloric acid is added,and the mixture is then again concentrated and dried under high vacuum.32 mg (67.8% of theory) of the title compound are obtained.

¹H NMR (400 MHz, methanol-d₄): δ=8.46 (s, 1H), 8.11 (s, 1H), 8.01-7.93(m, 2H), 7.89 (d, 1H), 7.49 (dd, 1H), 7.58 (d, 1H), 7.56-7.48 (m, 2H),4.46 (m, 1H), 3.83 (m, 1H), 3.50 (m, 1H), 3.44-3.24 (m, 4H), 2.38 (m,1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H) ppm.

HPLC: R_(t)=4.6 min (Method H)

MS (ESIpos): m/z=406 (M+H)⁺ (free base).

EXAMPLE 987-[(Z)-Amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzo-thiophene-2-carboxamidedihydrochloride

120 mg (0.43 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-cyano-1-benzo-thiophene-2-carboxamidehydrochloride, 45.0 mg (0.65 mmol) of hydroxylamine hydrochloride and119.2 mg (0.86 mmol) of potassium carbonate in 1.5 ml of an 8:1 mixtureof water and ethanol are heated at 80° C. for 18 h. The mixture ispurified by preparative HPLC. The product fractions are combined andconcentrated, acetonitrile and 1N aqueous hydrochloric acid (3:1) areadded and the mixture is then again concentrated and dried under highvacuum. 58 mg (30.3% of theory) of the title compound are obtained.

¹H NMR (300 MHz, methanol-d₄): δ=8.34 (s, 1H), 8.23 (d, 1H), 7.73 (d,1H), 7.65 (dd, 1H), 4.48 (m, 1H), 3.82 (m, 1H), 3.56 (m, 1H), 3.48-3.16(m, 4H), 2.39 (m, 1H), 2.30 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H) ppm.

HPLC: R_(t)=2.8 min (Method H)

MS (ESIpos): m/z=345 (M+H)⁺ (free base).

1. A compound of the formula

in which R¹ represents 1-azabicyclo[2.2.2]oct-3-yl, R² representshydrogen or C₁-C₆-alkyl, R³ represents hydrogen, halogen or C₁-C₆-alkyl,A represents oxygen or sulfur, and the ring B represents benzo, pyrido,pyrimido, pyridazo or pyridazino which are optionally substituted byradicals selected from the group consisting of hydrogen, halogen,C₁-C₆-alkanoyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy,nitro, amino, C₁-C₆-acylamino, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylamino, heteroarylcarbonylamino,arylcarbonylamino, C₁-C₄-alkylsulfonyl-amino,di-(C₁-C₄-alkylsulfonyl)amino, arylsulfonylamino, di(arylsulfonyl)amino,C₃-C₆-cycloalkylcarbonylmethyl, 1,3-dioxa-propane-1,3-diyl,amino(hydroxyimino)methyl and benzo, or a salt, a solvate or a solvateof a salt thereof.
 2. A compound of the formula (I) as claimed in claim1, in which R¹ represents 1-azabicyclo[2.2.2]oct-3-yl, R² representshydrogen or (C₁-C₆)-alkyl, R³ represents hydrogen, halogen or(C₁-C₆)-alkyl, A represents oxygen or sulfur, and the ring B representsbenzo, pyrido, pyrimido, pyridazo or pyridazino which are optionallysubstituted by radicals selected from the group consisting of hydrogen,halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy,nitro, amino, formamido, acetamido, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkylthio and benzo, or a salt, a solvate or a solvate of a saltthereof.
 3. A compound of the formula (I) as claimed in claim 1, inwhich R¹ represents 1-azabicyclo[2.2.2]oct-3-yl, R² represents hydrogen,R³ represents hydrogen, chlorine, fluorine or methyl, A representsoxygen or sulfur, and the ring B represents benzo or pyrido, where benzoor pyrido is optionally substituted by 1 to 3 radicals selected from thegroup consisting of hydrogen, halogen, formyl, carbamoyl, cyano,trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido,C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-alkylamino,furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino,di(phenylsulfonyl)amino, cyclopropylcarbonylmethyl,1,3-dioxapropane-1,3-diyl, amino(hydroxyimino)methyl and benzo, or asalt, a solvate or a solvate of a salt thereof.
 4. A compound as claimedin claim 1 of the formula (I), where R¹ represents(3R)-1-azabicyclo[2.2.2]oct-3-yl, and R², R³, A and the ring B are asdefined in claim
 1. 5. A compound as claimed in claim 1, of the formula(I), where R¹ represents (3R)-1-azabicyclo[2.2.2]oct-3-yl, R² and R³represent hydrogen, A represents sulfur, and the ring B represents benzoor pyrido, where benzo and pyrido are optionally substituted by 1 to 3radicals selected from the group consisting of hydrogen, halogen, cyano,trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamidoand C₁-C₄-alkyl, or a salt, a solvate or a solvate of a salt thereof. 6.A compound as claimed in claim 1 of the formula

in which R¹ represents 1-azabicyclo[2.2.2]oct-3-yl, R² representshydrogen or C₁-C₆-alkyl, R³ represents hydrogen, halogen or C₁-C₆-alkyl,A represents oxygen or sulfur, and Z represents hydrogen, halogen,formyl, carbamoyl, cyano, trifluoro-methyl, trifluoromethoxy, nitro,amino, formamido, acetamido, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylamino, heteroaryl-carbonylamino, arylcarbonylamino,C₁-C₄-alkylsulfonylamino, di(arylsulfonyl)amino,C₃-C₆-cycloalkylcarbonylmethyl or amino-(hydroxyimino)methyl, or a salt,a solvate or a solvate of a salt thereof.
 7. A compound as claimed inclaim 1 of the formula (Ia), in which R¹ represents1-azabicyclo[2.2.2]oct-3-yl, R² represents hydrogen, R³ representshydrogen, chlorine, fluorine or methyl, A represents oxygen or sulfur,and Z represents hydrogen, halogen, formyl, carbamoyl, cyano,trifluoro-methyl, trifluoromethoxy, nitro, amino, formamido, acetamido,methyl, ethyl, methoxy, ethoxy, C₁-C₄-alkylamino, furylcarbonylamino,phenylcarbonylamino, methylsulfonylamino, di(phenylsulfonyl)amino,cyclopropylcarbonylmethyl or amino(hydroxyimino)methyl, or a salt, asolvate or a solvate of a salt thereof.
 8. A compound as claimed inclaim 1 of the formula (Ia), in which R¹ represents(3R)-1-azabicyclo[2.2.2]oct-3-yl, R² represents hydrogen, R³ representshydrogen, chlorine, fluorine or methyl, A represents oxygen or sulfur,and Z represents hydrogen, halogen, formyl, carbamoyl, cyano,trifluoro-methyl, trifluoromethoxy, nitro, amino, formamido, acetamido,methyl, ethyl, methoxy, ethoxy, C₁-C₄-alkylamino, furylcarbonylamino,phenylcarbonylamino, methylsulfonylamino, di(phenylsulfonyl)amino,cyclopropylcarbonylmethyl or amino(hydroxyimino)methyl, or a salt, asolvate or a solvate of a salt thereof.
 9. A process for preparingcompounds of the formula (I) as claimed in claim 1, characterized inthat compounds of the formulaR¹R²NH   (II), in which R¹ and R² are as defined in claim 1 are reactedwith a compound of the formula

in which R³, A and the ring B are as defined in claim 1 and X representshydroxy or a suitable leaving group, in an inert solvent, if appropriatein the presence of a condensing agent and if appropriate in the presenceof a base.
 10. A compound as claimed in any of claims 1 to 8 for thetreatment and/or prophylaxis of diseases.
 11. A medicament comprising atleast one of the compounds as claimed in any of claims 1 to 8 in amixture with at least one pharmaceutically acceptable, essentiallynontoxic carrier or excipient.
 12. The use of compounds as claimed inany of claims 1 to 8 for preparing a medicament for improvingperception, concentration, learning and/or memory.
 13. The use ofcompounds as claimed in any of claims 1 to 8 for preparing a medicamentfor the treatment and/or prophylaxis of impairments of perception,concentration, learning and/or memory.
 14. A medicament as claimed inclaim 11 for the treatment and/or prophylaxis of impairments ofperception, concentration, learning and/or memory.
 15. A method forcontrolling in impairments of perception, concentration, learning and/ormemory humans or animals by administering an effective amount of acompound as claimed in claims 1 to 8.